1-150559429-C-A

Position:

chr1-150559429-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_019032.6(ADAMTSL4):c.2906C>A(p.Ala969Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,506 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0094 ( 9 hom., cov: 33)

Exomes 𝑓: 0.014 ( 193 hom. )

Consequence

ADAMTSL4
NM_019032.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.433

Variant links:

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]

ADAMTSL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057342947).

BP6

Variant 1-150559429-C-A is Benign according to our data. Variant chr1-150559429-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 261078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-150559429-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00945 (1438/152240) while in subpopulation NFE AF= 0.0156 (1064/67994). AF 95% confidence interval is 0.0149. There are 9 homozygotes in gnomad4. There are 710 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL4	NM_019032.6 linkuse as main transcript	c.2906C>A	p.Ala969Asp	missense_variant	17/19	ENST00000271643.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTSL4	ENST00000271643.9 linkuse as main transcript	c.2906C>A	p.Ala969Asp	missense_variant	17/19	5	NM_019032.6	P1	Q6UY14-1

Frequencies

GnomAD3 genomes

AF:

0.00945

AC:

1438

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0156

Gnomad OTH

AF:

0.00910

GnomAD3 exomes

AF:

0.00938

AC:

2331

AN:

248514

Hom.:

AF XY:

0.00909

AC XY:

1224

AN XY:

134656

show subpopulations

Gnomad AFR exome

AF:

0.00226

Gnomad AMR exome

AF:

0.00362

Gnomad ASJ exome

AF:

0.00271

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.0159

Gnomad OTH exome

AF:

0.00951

GnomAD4 exome

AF:

0.0138

AC:

20102

AN:

1461266

Hom.:

193

Cov.:

AF XY:

0.0134

AC XY:

9717

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.00349

Gnomad4 ASJ exome

AF:

0.00233

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00116

Gnomad4 FIN exome

AF:

0.0129

Gnomad4 NFE exome

AF:

0.0166

Gnomad4 OTH exome

AF:

0.00990

GnomAD4 genome

AF:

0.00945

AC:

1438

AN:

152240

Hom.:

Cov.:

AF XY:

0.00954

AC XY:

710

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00243

Gnomad4 AMR

AF:

0.00654

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0119

Gnomad4 NFE

AF:

0.0156

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.00906

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0153

AC:

132

ExAC

AF:

0.00926

AC:

1124

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0136

EpiControl

AF:

0.0127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2024	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ectopia lentis 2, isolated, autosomal recessive

Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Ectopia lentis et pupillae

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.0018

T;.;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.46

.;T;T

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.88

L;.;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.75

N;N;N

REVEL

Benign

0.020

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.55

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.12

MVP

0.37

MPC

0.19

ClinPred

0.0049

GERP RS

-0.12

Varity_R

0.14

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over