rs147543583

chr2-219556598-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.4192G>A(p.Val1398Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00622 in 1,613,984 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1398V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0051 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0063 ( 65 hom. )

Consequence

OBSL1
NM_015311.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.80

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=0.008137077).

BP6

Variant 2-219556598-C-T is Benign according to our data. Variant chr2-219556598-C-T is described in ClinVar as [Benign]. Clinvar id is 235404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219556598-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00511 (779/152316) while in subpopulation SAS AF= 0.0186 (90/4826). AF 95% confidence interval is 0.0155. There are 5 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSL1	NM_015311.3 linkuse as main transcript	c.4192G>A	p.Val1398Ile	missense_variant	13/21	ENST00000404537.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSL1	ENST00000404537.6 linkuse as main transcript	c.4192G>A	p.Val1398Ile	missense_variant	13/21	1	NM_015311.3	P1	O75147-3

Frequencies

GnomAD3 genomes

AF:

0.00513

AC:

781

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00576

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00647

AC:

1613

AN:

249158

Hom.:

AF XY:

0.00738

AC XY:

998

AN XY:

135214

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00429

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0203

Gnomad FIN exome

AF:

0.00650

Gnomad NFE exome

AF:

0.00551

Gnomad OTH exome

AF:

0.00496

GnomAD4 exome

AF:

0.00633

AC:

9257

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

4942

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00411

Gnomad4 ASJ exome

AF:

0.00295

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0200

Gnomad4 FIN exome

AF:

0.00592

Gnomad4 NFE exome

AF:

0.00577

Gnomad4 OTH exome

AF:

0.00735

GnomAD4 genome

AF:

0.00511

AC:

779

AN:

152316

Hom.:

Cov.:

AF XY:

0.00529

AC XY:

394

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00192

Gnomad4 AMR

AF:

0.00484

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0186

Gnomad4 FIN

AF:

0.00603

Gnomad4 NFE

AF:

0.00576

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00469

Hom.:

Bravo

AF:

0.00442

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00164

AC:

ESP6500EA

AF:

0.00718

AC:

ExAC

AF:

0.00633

AC:

767

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00605

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 15, 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

0.075

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

Cadd

Benign

0.17

Dann

Benign

0.84

DEOGEN2

Benign

0.015

T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.54

T;T;T

MetaRNN

Benign

0.0081

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.39

N;.;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.61

N;N;.

REVEL

Benign

0.0090

Sift

Benign

0.33

T;T;.

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0060

B;.;.

Vest4

0.042

MVP

0.26

MPC

0.13

ClinPred

0.0015

GERP RS

-8.7

Varity_R

0.026

gMVP

0.19

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