1-228276575-T-G

Position:

• chr1-228276575-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001386125.1(OBSCN):​c.7471T>G​(p.Phe2491Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F2491L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07773107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OBSCN	NM_001386125.1	c.7471T>G	p.Phe2491Val	missense_variant	26/116	ENST00000680850.1	NP_001373054.1
OBSCN	NM_001271223.3	c.7471T>G	p.Phe2491Val	missense_variant	26/116		NP_001258152.2
OBSCN	NM_001098623.2	c.6346T>G	p.Phe2116Val	missense_variant	22/105		NP_001092093.2
OBSCN	NM_052843.4	c.6346T>G	p.Phe2116Val	missense_variant	22/81		NP_443075.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OBSCN	ENST00000680850.1	c.7471T>G	p.Phe2491Val	missense_variant	26/116		NM_001386125.1	ENSP00000505517.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.53
DEOGEN2	Benign	0.015	.;T;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.53	T;T;T;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.94	N;N;.;.;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.0	N;N;.;.;.
REVEL	Benign	0.089
Sift	Benign	0.066	T;D;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;.
Polyphen		0.077	B;B;.;.;B
Vest4		0.17
MutPred		0.46		Gain of MoRF binding (P = 0.0778);Gain of MoRF binding (P = 0.0778);.;.;Gain of MoRF binding (P = 0.0778);
MVP		0.22
MPC		0.14
ClinPred		0.39	T
GERP RS		4.2
Varity_R		0.081
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1188722; hg19: chr1-228464276;