rs72957510

Positions:

chr2-219557964-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015311.3(OBSL1):c.3649G>A(p.Glu1217Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,608,856 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0063 ( 37 hom. )

Consequence

OBSL1
NM_015311.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.773

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004442841).

BP6

Variant 2-219557964-C-T is Benign according to our data. Variant chr2-219557964-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 193901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219557964-C-T is described in Lovd as [Likely_benign]. Variant chr2-219557964-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00711 (1083/152314) while in subpopulation AFR AF= 0.0138 (573/41574). AF 95% confidence interval is 0.0128. There are 3 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OBSL1	NM_015311.3 linkuse as main transcript	c.3649G>A	p.Glu1217Lys	missense_variant	11/21	ENST00000404537.6	NP_056126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OBSL1	ENST00000404537.6 linkuse as main transcript	c.3649G>A	p.Glu1217Lys	missense_variant	11/21	1	NM_015311.3	ENSP00000385636	P1	O75147-3

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1082

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00612

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00514

AC:

1191

AN:

231816

Hom.:

AF XY:

0.00494

AC XY:

632

AN XY:

127826

show subpopulations

Gnomad AFR exome

AF:

0.0162

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00226

Gnomad FIN exome

AF:

0.00269

Gnomad NFE exome

AF:

0.00719

Gnomad OTH exome

AF:

0.00416

GnomAD4 exome

AF:

0.00626

AC:

9118

AN:

1456542

Hom.:

Cov.:

AF XY:

0.00618

AC XY:

4476

AN XY:

724590

show subpopulations

Gnomad4 AFR exome

AF:

0.0151

Gnomad4 AMR exome

AF:

0.00220

Gnomad4 ASJ exome

AF:

0.00207

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00234

Gnomad4 FIN exome

AF:

0.00279

Gnomad4 NFE exome

AF:

0.00701

Gnomad4 OTH exome

AF:

0.00507

GnomAD4 genome

AF:

0.00711

AC:

1083

AN:

152314

Hom.:

Cov.:

AF XY:

0.00667

AC XY:

497

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0138

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00216

Gnomad4 NFE

AF:

0.00612

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00655

Hom.:

Bravo

AF:

0.00773

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.0106

AC:

ESP6500EA

AF:

0.00551

AC:

ExAC

AF:

0.00553

AC:

666

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 02, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2015	- -

3M syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

T;.;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.74

T;T;T

MetaRNN

Benign

0.0044

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.99

L;.;L

MutationTaster

Benign

0.59

D;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.38

N;N;.

REVEL

Benign

0.032

Sift

Benign

0.038

D;T;.

Sift4G

Benign

0.54

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.10

MVP

0.27

MPC

0.19

ClinPred

0.0087

GERP RS

1.4

Varity_R

0.077

gMVP

0.43

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