2-219570298-T-G

Variant summary

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

The NM_015311.3(OBSL1):c.935A>C(p.Lys312Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,126 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OBSL1 NM_015311.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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]

INHA (HGNC:6065): (inhibin subunit alpha) This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate multiple peptide products, including the alpha subunit of the inhibin A and B protein complexes. These complexes negatively regulate follicle stimulating hormone secretion from the pituitary gland. Inhibins have also been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. Mutations in this gene may be associated with male infertility and premature ovarian failure in female human patients. [provided by RefSeq, Aug 2016]

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=0.17827979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OBSL1	NM_015311.3	c.935A>C	p.Lys312Thr	missense_variant	1/21	ENST00000404537.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OBSL1	ENST00000404537.6	c.935A>C	p.Lys312Thr	missense_variant	1/21	1	NM_015311.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457910 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724724

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

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 AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 312 of the OBSL1 protein (p.Lys312Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OBSL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1359071). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.10	N;.;N;N
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.44	N;N;.;N
REVEL	Benign	0.16
Sift	Benign	0.030	D;D;.;T
Sift4G	Uncertain	0.037	D;D;D;D
Polyphen		0.91	P;.;.;D
Vest4		0.23
MutPred		0.50		Loss of ubiquitination at K312 (P = 0.0326);Loss of ubiquitination at K312 (P = 0.0326);Loss of ubiquitination at K312 (P = 0.0326);Loss of ubiquitination at K312 (P = 0.0326);
MVP		0.58
MPC		0.50
ClinPred		0.69	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.52

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: rs1697244489; hg19: chr2-220435020;