rs10749657

chr1-150558574-G-Achr1-150558574-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019032.6(ADAMTSL4):c.2484G>A(p.Pro828=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 1,613,870 control chromosomes in the GnomAD database, including 601,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55558 hom., cov: 32)
  • Exomes 𝑓: 0.86 (546343 hom.)
• Consequence: ADAMTSL4 NM_019032.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.85

Genes affected

ADAMTSL4 (HGNC:19706): (ADAMTS like 4) This gene is a member of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-like gene family and encodes a protein with seven thrombospondin type 1 repeats. The thrombospondin type 1 repeat domain is found in many proteins with diverse biological functions including cellular adhesion, angiogenesis, and patterning of the developing nervous system. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-150558574-G-A is Benign according to our data. Variant chr1-150558574-G-A is described in ClinVar as [Benign]. Clinvar id is 261077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150558574-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL4	NM_019032.6	c.2484G>A	p.Pro828=	synonymous_variant	15/19	ENST00000271643.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTSL4	ENST00000271643.9	c.2484G>A	p.Pro828=	synonymous_variant	15/19	5	NM_019032.6	P1

Frequencies

GnomAD3 genomes AF: 0.854 AC: 129867 AN: 152062 Hom.: 55511 Cov.: 32

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.844

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.910

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.832

GnomAD3 exomes AF: 0.870 AC: 218661 AN: 251226 Hom.: 95441 AF XY: 0.871 AC XY: 118309 AN XY: 135864

Gnomad AFR exome AF: 0.839

Gnomad AMR exome AF: 0.885

Gnomad ASJ exome AF: 0.816

Gnomad EAS exome AF: 0.977

Gnomad SAS exome AF: 0.902

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.848

Gnomad OTH exome AF: 0.853

GnomAD4 exome AF: 0.864 AC: 1262936 AN: 1461690 Hom.: 546343 Cov.: 86 AF XY: 0.864 AC XY: 628598 AN XY: 727166

Gnomad4 AFR exome AF: 0.835

Gnomad4 AMR exome AF: 0.880

Gnomad4 ASJ exome AF: 0.819

Gnomad4 EAS exome AF: 0.966

Gnomad4 SAS exome AF: 0.901

Gnomad4 FIN exome AF: 0.879

Gnomad4 NFE exome AF: 0.859

Gnomad4 OTH exome AF: 0.860

GnomAD4 genome AF: 0.854 AC: 129972 AN: 152180 Hom.: 55558 Cov.: 32 AF XY: 0.857 AC XY: 63755 AN XY: 74380

Gnomad4 AFR AF: 0.841

Gnomad4 AMR AF: 0.844

Gnomad4 ASJ AF: 0.820

Gnomad4 EAS AF: 0.979

Gnomad4 SAS AF: 0.912

Gnomad4 FIN AF: 0.875

Gnomad4 NFE AF: 0.851

Gnomad4 OTH AF: 0.830

Alfa AF: 0.846 Hom.: 29682

Bravo AF: 0.850

Asia WGS AF: 0.889 AC: 3091 AN: 3478

EpiCase AF: 0.836

EpiControl AF: 0.832

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ectopia lentis et pupillae Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Ectopia lentis 2, isolated, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.13
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs10749657; hg19: chr1-150531050; COSMIC: COSV55008654; COSMIC: COSV55008654;