NM_024700.4:c.1097A>G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3PM2PP3PP5BP4

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). ClinVar reports functional evidence for this variant: "SCV001976578: 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)." and additional evidence is available in ClinVar.

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: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

SNIP1 links:

ENSG00000307694 (HGNC:):

ENSG00000307694 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_024700.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001976578: 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).; SCV005352799: 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).

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024700.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNIP1	NM_024700.4	MANE Select	c.1097A>G	p.Glu366Gly	missense	Exon 4 of 4	NP_078976.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SNIP1	ENST00000296215.8	TSL:1 MANE Select	c.1097A>G	p.Glu366Gly	missense	Exon 4 of 4	ENSP00000296215.5	Q8TAD8
SNIP1	ENST00000638725.1	TSL:2	n.1609A>G		non_coding_transcript_exon	Exon 2 of 2
ENSG00000307694	ENST00000827919.1		n.534-2293T>C		intron	N/A

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Psychomotor retardation, epilepsy, and craniofacial dysmorphism (2)

not provided (1)

not specified (1)

SNIP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over