chr9-133536785-G-C

Variant names:

• chr9-133536785-G-C
• rs777512904
• NM_014694.4:c.73G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014694.4(ADAMTSL2):​c.73G>C​(p.Val25Leu) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ADAMTSL2 NM_014694.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.520

Genes affected

ADAMTSL2 (HGNC:14631): (ADAMTS like 2) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and ADAMTS-like protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The protein encoded by this gene lacks the protease domain, and is therefore of a member of the the ADAMTS-like protein subfamily. It is a secreted glycoprotein that binds the cell surface and extracellular matrix; it also interacts with latent transforming growth factor beta binding protein 1. Mutations in this gene have been associated with geleophysic dysplasia. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0476214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL2	NM_014694.4	c.73G>C	p.Val25Leu	missense_variant	Exon 2 of 19	ENST00000651351.2	NP_055509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL2	ENST00000651351.2	c.73G>C	p.Val25Leu	missense_variant	Exon 2 of 19		NM_014694.4	ENSP00000498961.2
ADAMTSL2	ENST00000393061.7	c.400G>C	p.Val134Leu	missense_variant	Exon 2 of 19	1		ENSP00000376781.3
ADAMTSL2	ENST00000354484.8	c.73G>C	p.Val25Leu	missense_variant	Exon 2 of 19	1		ENSP00000346478.4
ADAMTSL2	ENST00000393060.1	c.73G>C	p.Val25Leu	missense_variant	Exon 2 of 19	1		ENSP00000376780.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251008 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.9
DANN	Benign	0.80
DEOGEN2	Benign	0.0090	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.61	.;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.032
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.17
MutPred		0.20		Loss of loop (P = 0.0603);.;Loss of loop (P = 0.0603);
MVP		0.22
MPC		0.42
ClinPred		0.034	T
GERP RS		0.30
Varity_R		0.051
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777512904; hg19: chr9-136401907;