2-219570312-A-G

Position:

chr2-219570312-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015311.3(OBSL1):c.921T>C(p.Leu307=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.885 in 1,611,404 control chromosomes in the GnomAD database, including 634,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L307L?) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.81 ( 51741 hom., cov: 35)

Exomes 𝑓: 0.89 ( 582974 hom. )

Consequence

OBSL1
NM_015311.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.333

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:

INHA (HGNC:6065): (inhibin subunit alpha) This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate multiple peptide products, including the alpha subunit of the inhibin A and B protein complexes. These complexes negatively regulate follicle stimulating hormone secretion from the pituitary gland. Inhibins have also been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. Mutations in this gene may be associated with male infertility and premature ovarian failure in female human patients. [provided by RefSeq, Aug 2016]

INHA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 2-219570312-A-G is Benign according to our data. Variant chr2-219570312-A-G is described in ClinVar as [Benign]. Clinvar id is 193382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219570312-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.333 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSL1	NM_015311.3 linkuse as main transcript	c.921T>C	p.Leu307=	synonymous_variant	1/21	ENST00000404537.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSL1	ENST00000404537.6 linkuse as main transcript	c.921T>C	p.Leu307=	synonymous_variant	1/21	1	NM_015311.3	P1	O75147-3

Frequencies

GnomAD3 genomes

AF:

0.814

AC:

123845

AN:

152132

Hom.:

51711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.611

Gnomad AMI

AF:

0.921

Gnomad AMR

AF:

0.830

Gnomad ASJ

AF:

0.862

Gnomad EAS

AF:

0.905

Gnomad SAS

AF:

0.834

Gnomad FIN

AF:

0.920

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.904

Gnomad OTH

AF:

0.838

GnomAD3 exomes

AF:

0.865

AC:

208361

AN:

240848

Hom.:

90925

AF XY:

0.870

AC XY:

114187

AN XY:

131302

show subpopulations

Gnomad AFR exome

AF:

0.605

Gnomad AMR exome

AF:

0.830

Gnomad ASJ exome

AF:

0.854

Gnomad EAS exome

AF:

0.915

Gnomad SAS exome

AF:

0.833

Gnomad FIN exome

AF:

0.920

Gnomad NFE exome

AF:

0.904

Gnomad OTH exome

AF:

0.871

GnomAD4 exome

AF:

0.892

AC:

1301872

AN:

1459154

Hom.:

582974

Cov.:

AF XY:

0.891

AC XY:

646818

AN XY:

725614

show subpopulations

Gnomad4 AFR exome

AF:

0.599

Gnomad4 AMR exome

AF:

0.834

Gnomad4 ASJ exome

AF:

0.857

Gnomad4 EAS exome

AF:

0.886

Gnomad4 SAS exome

AF:

0.837

Gnomad4 FIN exome

AF:

0.916

Gnomad4 NFE exome

AF:

0.909

Gnomad4 OTH exome

AF:

0.876

GnomAD4 genome

AF:

0.814

AC:

123927

AN:

152250

Hom.:

51741

Cov.:

AF XY:

0.815

AC XY:

60689

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.611

Gnomad4 AMR

AF:

0.830

Gnomad4 ASJ

AF:

0.862

Gnomad4 EAS

AF:

0.905

Gnomad4 SAS

AF:

0.835

Gnomad4 FIN

AF:

0.920

Gnomad4 NFE

AF:

0.904

Gnomad4 OTH

AF:

0.839

Alfa

AF:

0.886

Hom.:

72540

Bravo

AF:

0.799

Asia WGS

AF:

0.857

AC:

2981

AN:

3478

EpiCase

AF:

0.903

EpiControl

AF:

0.900

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

3M syndrome 2

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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