chr1-228211818-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

7 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 523062.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSCN	NM_001386125.1 link	c.35T>A	p.Phe12Tyr	missense_variant	Exon 2 of 116	ENST00000680850.1	NP_001373054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSCN	ENST00000680850.1 link	c.35T>A	p.Phe12Tyr	missense_variant	Exon 2 of 116		NM_001386125.1	ENSP00000505517.1		A0A7P0Z489

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

GnomAD2 exomes

AF:

0.00339

AC:

692

AN:

204082

AF XY:

0.00357

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 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

African (AFR)

AF:

0.000933

AC:

AN:

32166

American (AMR)

AF:

0.00251

AC:

AN:

39072

Ashkenazi Jewish (ASJ)

AF:

0.00160

AC:

AN:

23120

East Asian (EAS)

AF:

0.00

AC:

AN:

38908

South Asian (SAS)

AF:

0.000971

AC:

AN:

79260

European-Finnish (FIN)

AF:

0.00164

AC:

AN:

49998

Middle Eastern (MID)

AF:

0.00306

AC:

AN:

4906

European-Non Finnish (NFE)

AF:

0.00570

AC:

6180

AN:

1084530

Other (OTH)

AF:

0.00503

AC:

291

AN:

57844

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

400

800

1201

1601

2001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

242

484

726

968

1210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00320

AC:

486

AN:

151870

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

207

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

41452

American (AMR)

AF:

0.00288

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.000834

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.000756

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00533

AC:

362

AN:

67890

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OBSCN: PP3, BS2 -

OBSCN-related disorder

Benign:1

May 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.076

.;T;.;.;T

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

PhyloP100

6.2

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

PromoterAI

-0.0052

Neutral

(source)

Varity_R

0.74

gMVP

0.64

Mutation Taster

=259/41

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over