chr1-37537781-A-C

Position:

chr1-37537781-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024700.4(SNIP1):c.1158T>G(p.Asp386Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,614,014 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D386N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

SNIP1
NM_024700.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.25

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 links:

LOC105378649 (HGNC:):

LOC105378649 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0053956807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNIP1	NM_024700.4 linkuse as main transcript	c.1158T>G	p.Asp386Glu	missense_variant	4/4	ENST00000296215.8
LOC105378649	XR_947190.3 linkuse as main transcript	n.621-908A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNIP1	ENST00000296215.8 linkuse as main transcript	c.1158T>G	p.Asp386Glu	missense_variant	4/4	1	NM_024700.4	P1
SNIP1	ENST00000638725.1 linkuse as main transcript	n.1670T>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000279

AC:

AN:

251306

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000133

AC:

195

AN:

1461798

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000944

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000197

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 30, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 06, 2024	The c.1158T>G (p.D386E) alteration is located in exon 4 (coding exon 4) of the SNIP1 gene. This alteration results from a T to G substitution at nucleotide position 1158, causing the aspartic acid (D) at amino acid position 386 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 386 of the SNIP1 protein (p.Asp386Glu). This variant is present in population databases (rs368368736, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SNIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 252743). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Benign

0.065

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.039

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.52

M_CAP

Benign

0.012

MetaRNN

Benign

0.0054

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.63

MutationTaster

Benign

0.99

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.070

REVEL

Benign

0.054

Sift

Benign

0.20

Sift4G

Benign

0.73

Polyphen

0.0030

Vest4

0.16

MutPred

0.16

Gain of helix (P = 0.1736);

MVP

0.24

MPC

0.54

ClinPred

0.0084

GERP RS

-1.7

Varity_R

0.049

gMVP

0.15

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over