rs749541061

chr2-219559471-G-A

Variant summary

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

The NM_015311.3(OBSL1):c.2980C>T(p.Arg994Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,704 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R994H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

OBSL1
NM_015311.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.87

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:

(HGNC:):

links:

Genome browser will be placed here

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	UniProt
OBSL1	NM_015311.3 linkuse as main transcript	c.2980C>T	p.Arg994Cys	missense_variant	9/21	ENST00000404537.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSL1	ENST00000404537.6 linkuse as main transcript	c.2980C>T	p.Arg994Cys	missense_variant	9/21	1	NM_015311.3	P1	O75147-3
	ENST00000597192.1 linkuse as main transcript	n.389G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

248724

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

134876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Coarctation of aorta;C0018794:Heart block;C0018817:Atrial septal defect;C0018818:Ventricular septal defect;C0152415:Ankyloglossia;C0264353:Bronchomalacia;C0432123:Sagittal craniosynostosis;C1837658:Delayed gross motor development;C1850049:Clinodactyly of the 5th finger;C1858120:Generalized hypotonia;C1862095:Bilateral single transverse palmar creases;C4021164:Bicoronal synostosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 15, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 994 of the OBSL1 protein (p.Arg994Cys). This variant is present in population databases (rs749541061, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of 3M syndrome (PMID: 30755392). ClinVar contains an entry for this variant (Variation ID: 598981). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.27

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.28

T;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.90

L;.;L

MutationTaster

Benign

0.70

D;D;N

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.4

D;D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0080

D;D;.

Sift4G

Uncertain

0.010

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.58

MutPred

0.56

Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);

MVP

0.74

MPC

0.58

ClinPred

0.56

GERP RS

4.3

Varity_R

0.12

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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