rs435776

Variant names:

• chr1-228307089-G-A
• rs435776
• NM_001386125.1:c.14986G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-228307089-G-A
• chr1-228307089-G-C
• chr1-228307089-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001386125.1(OBSCN):​c.14986G>A​(p.Gly4996Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,613,582 control chromosomes in the GnomAD database, including 179,831 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (12840 hom., cov: 33)
  • Exomes 𝑓: 0.47 (166991 hom.)
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.596
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• rhabdomyolysis, susceptibility to, 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8668175E-4).
• BP6: Variant 1-228307089-G-A is Benign according to our data. Variant chr1-228307089-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060499.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386125.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSCN	NM_001386125.1	MANE Select	c.14986G>A	p.Gly4996Arg	missense	Exon 56 of 116	NP_001373054.1	Q5VST9-7
	OBSCN	NM_001271223.3		c.14986G>A	p.Gly4996Arg	missense	Exon 56 of 116	NP_001258152.2
	OBSCN	NM_001098623.2		c.12115G>A	p.Gly4039Arg	missense	Exon 45 of 105	NP_001092093.2	A0ABB0I190

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSCN	ENST00000680850.1	MANE Select	c.14986G>A	p.Gly4996Arg	missense	Exon 56 of 116	ENSP00000505517.1	Q5VST9-7
	OBSCN	ENST00000636476.2	TSL:1	c.12115G>A	p.Gly4039Arg	missense	Exon 44 of 104	ENSP00000489816.2	A0ABB0L580
	OBSCN	ENST00000570156.7	TSL:5	c.14986G>A	p.Gly4996Arg	missense	Exon 56 of 116	ENSP00000455507.2	A6NGQ3

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56382 AN: 151960 Hom.: 12838 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.394

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.378

GnomAD2 exomes AF: 0.410 AC: 101909 AN: 248620 AF XY: 0.415

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.202

Gnomad FIN exome AF: 0.561

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.469 AC: 686043 AN: 1461504 Hom.: 166991 Cov.: 66 AF XY: 0.466 AC XY: 338540 AN XY: 727026

African (AFR) AF: 0.0947 AC: 3169 AN: 33480

American (AMR) AF: 0.358 AC: 16001 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 10740 AN: 26132

East Asian (EAS) AF: 0.232 AC: 9192 AN: 39694

South Asian (SAS) AF: 0.334 AC: 28827 AN: 86252

European-Finnish (FIN) AF: 0.555 AC: 29627 AN: 53364

Middle Eastern (MID) AF: 0.323 AC: 1862 AN: 5766

European-Non Finnish (NFE) AF: 0.504 AC: 560642 AN: 1111762

Other (OTH) AF: 0.430 AC: 25983 AN: 60362

GnomAD4 genome AF: 0.371 AC: 56387 AN: 152078 Hom.: 12840 Cov.: 33 AF XY: 0.373 AC XY: 27688 AN XY: 74316

African (AFR) AF: 0.112 AC: 4642 AN: 41502

American (AMR) AF: 0.394 AC: 6023 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1424 AN: 3472

East Asian (EAS) AF: 0.224 AC: 1156 AN: 5160

South Asian (SAS) AF: 0.320 AC: 1542 AN: 4814

European-Finnish (FIN) AF: 0.571 AC: 6046 AN: 10580

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34275 AN: 67956

Other (OTH) AF: 0.374 AC: 788 AN: 2106

Alfa AF: 0.451 Hom.: 73152

Bravo AF: 0.340

TwinsUK AF: 0.510 AC: 1892

ALSPAC AF: 0.505 AC: 1947

ESP6500AA AF: 0.117 AC: 513

ESP6500EA AF: 0.494 AC: 4232

ExAC AF: 0.406 AC: 49236

Asia WGS AF: 0.260 AC: 908 AN: 3478

EpiCase AF: 0.480

EpiControl AF: 0.476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	OBSCN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.8
DANN	Benign	0.68
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.00019	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.60
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.033
Sift	Benign	0.46	T
Sift4G	Benign	0.21	T
Polyphen		0.058	B
Vest4		0.18
MutPred		0.45		Loss of sheet (P = 0.0315)
MPC		0.50
ClinPred		0.012	T
GERP RS		0.34
Varity_R		0.049
gMVP		0.072
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs435776; hg19: chr1-228494790; COSMIC: COSV52748925; COSMIC: COSV52748925;