2-219571114-G-A

Variant names:

• chr2-219571114-G-A
• rs191256186
• NM_015311.3:c.119C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/22 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 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015311.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	NM_015311.3	MANE Select	c.119C>T	p.Pro40Leu	missense	Exon 1 of 21	NP_056126.1
	OBSL1	NM_001173431.2		c.119C>T	p.Pro40Leu	missense	Exon 1 of 14	NP_001166902.1
	OBSL1	NM_001173408.2		c.119C>T	p.Pro40Leu	missense	Exon 1 of 9	NP_001166879.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OBSL1	ENST00000404537.6	TSL:1 MANE Select	c.119C>T	p.Pro40Leu	missense	Exon 1 of 21	ENSP00000385636.1
	OBSL1	ENST00000373873.8	TSL:1	c.119C>T	p.Pro40Leu	missense	Exon 1 of 9	ENSP00000362980.4
	OBSL1	ENST00000373876.5	TSL:5	c.119C>T	p.Pro40Leu	missense	Exon 1 of 20	ENSP00000362983.1

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

African (AFR) AF: 0.00 AC: 0 AN: 26818

American (AMR) AF: 0.00 AC: 0 AN: 27286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22506

East Asian (EAS) AF: 0.00 AC: 0 AN: 29270

South Asian (SAS) AF: 0.0000140 AC: 1 AN: 71650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5392

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047982

Other (OTH) AF: 0.00 AC: 0 AN: 54278

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.18
Sift	Benign	0.17	T
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.37
MutPred		0.53		Loss of catalytic residue at P39 (P = 0.0193)
MVP		0.76
MPC		1.4
ClinPred		0.12	T
GERP RS		2.7
PromoterAI		0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.8
Varity_R		0.10
gMVP		0.31
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs191256186; hg19: chr2-220435836;