chr1-228211818-T-A

Position:

chr1-228211818-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001386125.1(OBSCN):c.35T>A(p.Phe12Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00467 in 1,561,674 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F12V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0048 ( 26 hom. )

Consequence

OBSCN
NM_001386125.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.15

Variant links:

Genes affected

OBSCN (HGNC:15719): (obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF) The obscurin gene spans more than 150 kb, contains over 80 exons and encodes a protein of approximately 720 kDa. The encoded protein contains 68 Ig domains, 2 fibronectin domains, 1 calcium/calmodulin-binding domain, 1 RhoGEF domain with an associated PH domain, and 2 serine-threonine kinase domains. This protein belongs to the family of giant sacromeric signaling proteins that includes titin and nebulin, and may have a role in the organization of myofibrils during assembly and may mediate interactions between the sarcoplasmic reticulum and myofibrils. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

OBSCN links:

OBSCN-AS1 (HGNC:32047): (OBSCN antisense RNA 1)

OBSCN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015575349).

BP6

Variant 1-228211818-T-A is Benign according to our data. Variant chr1-228211818-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523062.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr1-228211818-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0032 (486/151870) while in subpopulation NFE AF= 0.00533 (362/67890). AF 95% confidence interval is 0.00488. There are 1 homozygotes in gnomad4. There are 207 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSCN	NM_001386125.1 linkuse as main transcript	c.35T>A	p.Phe12Tyr	missense_variant	2/116	ENST00000680850.1
OBSCN-AS1	NR_073155.1 linkuse as main transcript	n.234+1604A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSCN	ENST00000680850.1 linkuse as main transcript	c.35T>A	p.Phe12Tyr	missense_variant	2/116		NM_001386125.1	P4
OBSCN-AS1	ENST00000295012.5 linkuse as main transcript	n.239+1604A>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

487

AN:

151752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000833

Gnomad FIN

AF:

0.000756

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00533

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00339

AC:

692

AN:

204082

Hom.:

AF XY:

0.00357

AC XY:

400

AN XY:

112056

show subpopulations

Gnomad AFR exome

AF:

0.000930

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00213

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00104

Gnomad FIN exome

AF:

0.000986

Gnomad NFE exome

AF:

0.00581

Gnomad OTH exome

AF:

0.00390

GnomAD4 exome

AF:

0.00483

AC:

6810

AN:

1409804

Hom.:

Cov.:

AF XY:

0.00469

AC XY:

3260

AN XY:

695058

show subpopulations

Gnomad4 AFR exome

AF:

0.000933

Gnomad4 AMR exome

AF:

0.00251

Gnomad4 ASJ exome

AF:

0.00160

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000971

Gnomad4 FIN exome

AF:

0.00164

Gnomad4 NFE exome

AF:

0.00570

Gnomad4 OTH exome

AF:

0.00503

GnomAD4 genome

AF:

0.00320

AC:

486

AN:

151870

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

207

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000834

Gnomad4 FIN

AF:

0.000756

Gnomad4 NFE

AF:

0.00533

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00356

Hom.:

Bravo

AF:

0.00355

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000751

AC:

ESP6500EA

AF:

0.00571

AC:

ExAC

AF:

0.00355

AC:

426

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	OBSCN: PP3, BS1, BS2 -

OBSCN-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Benign

0.96

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

D;D;D;.;.

M_CAP

Benign

0.071

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

3.1

M;M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.8

N;N;N;.;.

REVEL

Pathogenic

0.67

Sift

Benign

0.093

T;T;T;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;D;.;.;D

Vest4

0.50

MVP

0.70

MPC

2.3

ClinPred

0.051

GERP RS

4.8

Varity_R

0.74

gMVP

0.64

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