2-219571114-G-A

Variant names:

• chr2-219571114-G-A
• NM_015311.3:c.119C>T

Variant summary

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

The NM_015311.3(OBSL1):​c.119C>T​(p.Pro40Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000759 in 1,317,850 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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. P40R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: OBSL1 NM_015311.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OBSL1	NM_015311.3	c.119C>T	p.Pro40Leu	missense_variant	Exon 1 of 21	ENST00000404537.6	NP_056126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OBSL1	ENST00000404537.6	c.119C>T	p.Pro40Leu	missense_variant	Exon 1 of 21	1	NM_015311.3	ENSP00000385636.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.59e-7 AC: 1 AN: 1317850 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 650914

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: 0.0000140

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.20	N;.;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.030	N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.17	T;T;.;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.99	D;.;.;P
Vest4		0.37
MutPred		0.53		Loss of catalytic residue at P39 (P = 0.0193);Loss of catalytic residue at P39 (P = 0.0193);Loss of catalytic residue at P39 (P = 0.0193);Loss of catalytic residue at P39 (P = 0.0193);
MVP		0.76
MPC		1.4
ClinPred		0.12	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.8
Varity_R		0.10
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-220435836;