Variant 2-219570326-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015311.3(OBSL1):c.907G>A(p.Val303Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

OBSL1
NM_015311.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.09

Variant links:

Genes affected

OBSL1 (HGNC:29092): (obscurin like cytoskeletal adaptor 1) Cytoskeletal adaptor proteins function in linking the internal cytoskeleton of cells to the cell membrane. This gene encodes a cytoskeletal adaptor protein, which is a member of the Unc-89/obscurin family. The protein contains multiple N- and C-terminal immunoglobulin (Ig)-like domains and a central fibronectin type 3 domain. Mutations in this gene cause 3M syndrome type 2. Alternatively spliced transcript variants encoding different isoforms have been found in this gene. [provided by RefSeq, Mar 2010]

OBSL1 links:

OBSL1 (HGNC:):

OBSL1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OBSL1	NM_015311.3 linkuse as main transcript	c.907G>A	p.Val303Met	missense_variant	1/21	ENST00000404537.6	NP_056126.1	O75147-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OBSL1	ENST00000404537.6 linkuse as main transcript	c.907G>A	p.Val303Met	missense_variant	1/21	1	NM_015311.3	ENSP00000385636.1		O75147-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000831

AC:

AN:

240802

Hom.:

AF XY:

0.00000761

AC XY:

AN XY:

131394

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459756

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726038

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

3M syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 30, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

0.0039

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

T;.;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.45

T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.6

L;.;L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.1

N;N;.;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.012

D;D;.;D

Sift4G

Uncertain

0.016

D;D;D;D

Polyphen

1.0

D;.;.;D

Vest4

0.39

MutPred

0.66

Gain of ubiquitination at K305 (P = 0.0661);Gain of ubiquitination at K305 (P = 0.0661);Gain of ubiquitination at K305 (P = 0.0661);Gain of ubiquitination at K305 (P = 0.0661);

MVP

0.56

MPC

0.64

ClinPred

0.92

GERP RS

3.6

Varity_R

0.25

gMVP

0.44

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