rs1039898

Positions:

• chr2-219565481-C-A
• chr2-219565481-C-G
• chr2-219565481-C-T

Variant summary

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

The ENST00000404537.6(OBSL1):​c.2168G>T​(p.Arg723Met) 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. R723K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OBSL1 ENST00000404537.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.308

Genes affected

OBSL1 (HGNC:29092): (obscurin like cytoskeletal adaptor 1) Cytoskeletal adaptor proteins function in linking the internal cytoskeleton of cells to the cell membrane. This gene encodes a cytoskeletal adaptor protein, which is a member of the Unc-89/obscurin family. The protein contains multiple N- and C-terminal immunoglobulin (Ig)-like domains and a central fibronectin type 3 domain. Mutations in this gene cause 3M syndrome type 2. Alternatively spliced transcript variants encoding different isoforms have been found in this gene. [provided by RefSeq, Mar 2010]

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=0.07366508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OBSL1	NM_015311.3	c.2168G>T	p.Arg723Met	missense_variant	6/21	ENST00000404537.6	NP_056126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OBSL1	ENST00000404537.6	c.2168G>T	p.Arg723Met	missense_variant	6/21	1	NM_015311.3	ENSP00000385636	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T;.;.;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.42	T;T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.074	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.34	N;.;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;N;.;N;N
REVEL	Benign	0.070
Sift	Uncertain	0.0020	D;D;.;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D
Polyphen		0.40	B;.;.;B;B
Vest4		0.25
MutPred		0.45		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;
MVP		0.34
MPC		0.44
ClinPred		0.52	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.076
gMVP		0.63

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: rs1039898; hg19: chr2-220430203; COSMIC: COSV54731761; COSMIC: COSV54731761;