1-228211970-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001386125.1(OBSCN):c.187G>A(p.Asp63Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00535 in 1,597,928 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (129 hom.)
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.75

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028885603).
• BP6: Variant 1-228211970-G-A is Benign according to our data. Variant chr1-228211970-G-A is described in ClinVar as [Benign]. Clinvar id is 3055327.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-228211970-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSCN	NM_001386125.1	c.187G>A	p.Asp63Asn	missense_variant	2/116	ENST00000680850.1
OBSCN-AS1	NR_073155.1	n.234+1452C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSCN	ENST00000680850.1	c.187G>A	p.Asp63Asn	missense_variant	2/116		NM_001386125.1	P4
OBSCN-AS1	ENST00000295012.5	n.239+1452C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1579 AN: 152110 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.0668

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0101 AC: 2156 AN: 212908 Hom.: 64 AF XY: 0.00924 AC XY: 1083 AN XY: 117216

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.0722

Gnomad SAS exome AF: 0.0105

Gnomad FIN exome AF: 0.00498

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00687

GnomAD4 exome AF: 0.00482 AC: 6962 AN: 1445702 Hom.: 129 Cov.: 72 AF XY: 0.00488 AC XY: 3502 AN XY: 717958

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.00365

Gnomad4 EAS exome AF: 0.0693

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.00444

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.00768

GnomAD4 genome AF: 0.0104 AC: 1582 AN: 152226 Hom.: 37 Cov.: 33 AF XY: 0.0105 AC XY: 778 AN XY: 74440

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.0668

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.0111

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0182 AC: 74

ESP6500EA AF: 0.00181 AC: 15

ExAC AF: 0.00920 AC: 1097

Asia WGS AF: 0.0330 AC: 114 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

OBSCN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as 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	Benign	0.23
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.52
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;.;.
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N;N;.;.;N
MutationTaster	Benign	0.63	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D;N;N;.;.
REVEL	Benign	0.22
Sift	Benign	0.52	T;T;T;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		0.85	P;P;.;.;P
Vest4		0.14
MVP		0.74
MPC		2.1
ClinPred		0.039	T
GERP RS		4.7
Varity_R		0.54
gMVP		0.61

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: rs117484136; hg19: chr1-228399671;