9-133537419-A-G

Position:

• chr9-133537419-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_014694.4(ADAMTSL2):​c.105A>G​(p.Thr35=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,341,662 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (5 hom.)
• Consequence: ADAMTSL2 NM_014694.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.74

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-133537419-A-G is Benign according to our data. Variant chr9-133537419-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3035152.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-2.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00253 (385/152224) while in subpopulation AFR AF= 0.00835 (347/41552). AF 95% confidence interval is 0.00763. There are 3 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTSL2	NM_014694.4	c.105A>G	p.Thr35=	synonymous_variant	3/19	ENST00000651351.2	NP_055509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTSL2	ENST00000651351.2	c.105A>G	p.Thr35=	synonymous_variant	3/19		NM_014694.4	ENSP00000498961	P1
ADAMTSL2	ENST00000393061.7	c.432A>G	p.Thr144=	synonymous_variant	3/19	1		ENSP00000376781
ADAMTSL2	ENST00000354484.8	c.105A>G	p.Thr35=	synonymous_variant	3/19	1		ENSP00000346478	P1
ADAMTSL2	ENST00000393060.1	c.105A>G	p.Thr35=	synonymous_variant	3/19	1		ENSP00000376780	P1

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 383 AN: 152106 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00833

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000736 AC: 91 AN: 123604 Hom.: 2 AF XY: 0.000524 AC XY: 35 AN XY: 66770

Gnomad AFR exome AF: 0.00852

Gnomad AMR exome AF: 0.000445

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000154

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.000206 AC: 245 AN: 1189438 Hom.: 5 Cov.: 30 AF XY: 0.000194 AC XY: 111 AN XY: 572904

Gnomad4 AFR exome AF: 0.00754

Gnomad4 AMR exome AF: 0.000619

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000287

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.000735

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152224 Hom.: 3 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74442

Gnomad4 AFR AF: 0.00835

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00286

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ADAMTSL2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.065
DANN	Benign	0.33

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: rs141636965; hg19: chr9-136402541;