rs191837710

chr1-228211818-T-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.15

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

ACMG classification

Verdict is Benign. Variant got -9 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. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSCN	NM_001386125.1	c.35T>A	p.Phe12Tyr	missense_variant	2/116	ENST00000680850.1
OBSCN-AS1	NR_073155.1	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	c.35T>A	p.Phe12Tyr	missense_variant	2/116		NM_001386125.1	P4
OBSCN-AS1	ENST00000295012.5	n.239+1604A>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 487 AN: 151752 Hom.: 1 Cov.: 33

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.: 1 AF XY: 0.00357 AC XY: 400 AN XY: 112056

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.: 26 Cov.: 72 AF XY: 0.00469 AC XY: 3260 AN XY: 695058

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.: 1 Cov.: 33 AF XY: 0.00279 AC XY: 207 AN XY: 74230

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.: 1

Bravo AF: 0.00355

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000751 AC: 3

ESP6500EA AF: 0.00571 AC: 47

ExAC AF: 0.00355 AC: 426

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

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

OBSCN-related condition 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	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Benign	0.96
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D;.;.
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
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	T
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

Other links and lift over

dbSNP: rs191837710; hg19: chr1-228399519;