rs387906986

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP3PP5BP4

The NM_024700.4(SNIP1):c.1097A>G(p.Glu366Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SNIP1
NM_024700.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 7.65

Publications

8 publications found

Variant links:

Genes affected

SNIP1 (HGNC:30587): (Smad nuclear interacting protein 1) This gene encodes a protein that contains a coiled-coil motif and C-terminal forkhead-associated (FHA) domain. The encoded protein functions as a transcriptional coactivator that increases c-Myc activity and inhibits transforming growth factor beta (TGF-beta) and nuclear factor kappa-B (NF-kB) signaling. The encoded protein also regulates the stability of cyclin D1 mRNA, and may play a role in cell proliferation and cancer progression. Mutations in this gene are a cause of psychomotor retardation, epilepsy, and craniofacial dysmorphism (PMRED). [provided by RefSeq, Mar 2012]

SNIP1 Gene-Disease associations (from GenCC):

psychomotor retardation, epilepsy, and craniofacial dysmorphism
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P

SNIP1 links:

ENSG00000307694 (HGNC:):

ENSG00000307694 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN [when max_spliceai, M_CAP, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

PP5

Variant 1-37537842-T-C is Pathogenic according to our data. Variant chr1-37537842-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30717.

BP4

Computational evidence support a benign effect (MetaRNN=0.4117362). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNIP1	NM_024700.4 link	c.1097A>G	p.Glu366Gly	missense_variant	Exon 4 of 4	ENST00000296215.8	NP_078976.2	Q8TAD8B1AK66
LOC105378649	XR_947190.3 link	n.621-847T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SNIP1	ENST00000296215.8 link	c.1097A>G	p.Glu366Gly	missense_variant	Exon 4 of 4	1	NM_024700.4	ENSP00000296215.5	Q8TAD8
SNIP1	ENST00000638725.1 link	n.1609A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
ENSG00000307694	ENST00000827919.1 link	n.534-2293T>C		intron_variant	Intron 1 of 2
SNIP1	ENST00000468040.2 link	n.*871A>G		downstream_gene_variant		5		ENSP00000492185.1	A0A1W2PRA0

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112008

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000630

Hom.:

Bravo

AF:

0.0000869

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Psychomotor retardation, epilepsy, and craniofacial dysmorphism

Pathogenic:2

Jan 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 22, 2022

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SNIP1 c.1097A>G p.(Glu366Gly) missense variant results in substitution of glutamic acid at amino acid position 366 with glycine. This variant has been reported in a homozygous state in at least 35 individuals from 21 interrelated Old Order Amish families diagnosed with neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures, with segregation noted in several families (Puffenbuerger et al. 2012; Ammous et al. 2021). This variant is reported in the Genome Aggregation Database in ten alleles at a frequency of 0.01096 in the Amish population (version 3.1.2). The variant is present in the C-terminus portion of the protein, which is known to interact with c-Myc, SMAD1 and SMAD2 (Puffenberger et al. 2012). Transient overexpression of wild-type and p.Glu353Gly Snip1 mouse protein (corresponding to human p.Glu366Gly protein) in mIMCD3 cells revealed the mutant protein to have a more aggregated appearance as compared to wild-type protein and also resulted in decreased protein levels suggestive of an unstable protein (Puffenberger et al. 2012). Multiple lines of computational evidence suggest the variant may have a deleterious impact on the gene or gene product. Based on the available evidence the c.1097A>G p.(Glu366Gly) variant is classified as likely pathogenic for neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures. -

SNIP1-related disorder

Pathogenic:1

Jun 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SNIP1 c.1097A>G variant is predicted to result in the amino acid substitution p.Glu366Gly. This variant has been reported in the homozygous state in three Old Order Amish patients with symptomatic epilepsy and skull dysplasia (Puffenberger et al. 2012. PubMed ID: 22279524). An additional large study detected this variant in the homozygous state in thirty-five affected Old Order Amish individuals with a neurodevelopmental disorder and varied clinical phenotypes (Ammous et al 2021. PubMed ID: 34570759). An in vitro mouse model found this variant results in a more aggregated localization in the nucleus compared to wild type and Western blot analysis suggested it is unstable (Puffenberger et al. 2012. PubMed ID: 22279524). Analysis of >5,000 Amish control samples indicated an allele frequency of 0.5% (Pennsylvania Amish) to 1.4% (Ohio/Indiana/Wisconsin Amish) in this founder population with no unaffected individuals being homozygous for this variant (Ammous et al 2021. PubMed ID: 34570759; Puffenberger et al. 2012. PubMed ID: 22279524). In summary, we interpret this variant as likely pathogenic. -

not specified

Uncertain:1

Dec 22, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1097A>G (p.E366G) alteration is located in exon 4 (coding exon 4) of the SNIP1 gene. This alteration results from a A to G substitution at nucleotide position 1097, causing the glutamic acid (E) at amino acid position 366 to be replaced by a glycine (G). Based on data from the Genome Aggregation Database (gnomAD), the SNIP1 c.1097A>G alteration was not observed, with coverage at this position. This alteration was reported homozygous in two Amish brothers with severe psychomotor delay, intractable seizures, bulbous nose, wide mouth and tongue, broad jaw with protuberant angles, short hands, short tapered fingers, and broad thumbs. A brain MRI showed enlarged ventricles, a thin corpus callosum, hypomyelination, and an irregular, undulating skull surface (Puffenberger, 2012). The p.E366 amino acid is conserved in available vertebrate species. The in silico prediction for the p.E366G alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 366 of the SNIP1 protein (p.Glu366Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive syndromic epilepsy and skull dysplasia (PMID: 22279524, 34570759). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30717). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SNIP1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SNIP1 function (PMID: 22279524). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.032

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.89

MutationAssessor

Benign

2.0

PhyloP100

7.6

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MutPred

0.40

Loss of stability (P = 0.0108);

MVP

0.65

MPC

1.0

ClinPred

0.98

GERP RS

6.2

Varity_R

0.95

gMVP

0.78

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over