1-228211804-C-A

Position:

• chr1-228211804-C-A

Variant summary

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

The NM_001386125.1(OBSCN):​c.21C>A​(p.Ser7Arg) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OBSCN NM_001386125.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.74

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 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=0.13596565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSCN	NM_001386125.1	c.21C>A	p.Ser7Arg	missense_variant	2/116	ENST00000680850.1
OBSCN-AS1	NR_073155.1	n.234+1618G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSCN	ENST00000680850.1	c.21C>A	p.Ser7Arg	missense_variant	2/116		NM_001386125.1	P4
OBSCN-AS1	ENST00000295012.5	n.239+1618G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1396698 Hom.: 0 Cov.: 72 AF XY: 0.00 AC XY: 0 AN XY: 686676

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.21C>A (p.S7R) alteration is located in exon 2 (coding exon 1) of the OBSCN gene. This alteration results from a C to A substitution at nucleotide position 21, causing the serine (S) at amino acid position 7 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.88
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.074	N
LIST_S2	Uncertain	0.93	D;D;D;.;.
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.9	M;M;.;.;M
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N;N;N;.;.
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.0050	D;D;D;D;.
Polyphen		1.0	D;D;.;.;D
Vest4		0.14
MutPred		0.30		Gain of MoRF binding (P = 0.0097);Gain of MoRF binding (P = 0.0097);Gain of MoRF binding (P = 0.0097);Gain of MoRF binding (P = 0.0097);Gain of MoRF binding (P = 0.0097);
MVP		0.42
MPC		2.2
ClinPred		0.88	D
GERP RS		-4.9
Varity_R		0.32
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-228399505;