1-150553568-G-C

Variant names:

• chr1-150553568-G-C
• rs41317515
• NM_019032.6:c.577G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019032.6(ADAMTSL4):​c.577G>C​(p.Ala193Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,613,072 control chromosomes in the GnomAD database, including 225,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22485 hom., cov: 28)
  • Exomes 𝑓: 0.52 (203049 hom.)
• Consequence: ADAMTSL4 NM_019032.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.17
• Publications: 36 publications found

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-AS2 (HGNC:40895): (ADAMTSL4 antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.249086E-6).
• BP6: Variant 1-150553568-G-C is Benign according to our data. Variant chr1-150553568-G-C is described in ClinVar as Benign. ClinVar VariationId is 261079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019032.6. 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
	ADAMTSL4	NM_019032.6	MANE Select	c.577G>C	p.Ala193Pro	missense	Exon 6 of 19	NP_061905.2
	ADAMTSL4	NM_001288608.2		c.577G>C	p.Ala193Pro	missense	Exon 6 of 20	NP_001275537.1
	ADAMTSL4	NM_001378596.1		c.577G>C	p.Ala193Pro	missense	Exon 6 of 19	NP_001365525.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL4	ENST00000271643.9	TSL:5 MANE Select	c.577G>C	p.Ala193Pro	missense	Exon 6 of 19	ENSP00000271643.4
	ADAMTSL4	ENST00000369038.6	TSL:1	c.577G>C	p.Ala193Pro	missense	Exon 4 of 17	ENSP00000358034.2
	ADAMTSL4	ENST00000369039.9	TSL:5	c.577G>C	p.Ala193Pro	missense	Exon 6 of 20	ENSP00000358035.5

Frequencies

GnomAD3 genomes AF: 0.542 AC: 81953 AN: 151122 Hom.: 22461 Cov.: 28

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.505

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.391

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.535

GnomAD2 exomes AF: 0.522 AC: 131133 AN: 251424 AF XY: 0.513

Gnomad AFR exome AF: 0.598

Gnomad AMR exome AF: 0.503

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.546

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.526

Gnomad OTH exome AF: 0.526

GnomAD4 exome AF: 0.525 AC: 767392 AN: 1461832 Hom.: 203049 Cov.: 73 AF XY: 0.519 AC XY: 377632 AN XY: 727226

African (AFR) AF: 0.598 AC: 20035 AN: 33480

American (AMR) AF: 0.497 AC: 22215 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11311 AN: 26134

East Asian (EAS) AF: 0.560 AC: 22216 AN: 39698

South Asian (SAS) AF: 0.408 AC: 35187 AN: 86258

European-Finnish (FIN) AF: 0.643 AC: 34330 AN: 53420

Middle Eastern (MID) AF: 0.501 AC: 2888 AN: 5768

European-Non Finnish (NFE) AF: 0.529 AC: 588004 AN: 1111962

Other (OTH) AF: 0.517 AC: 31206 AN: 60390

GnomAD4 genome AF: 0.542 AC: 82024 AN: 151240 Hom.: 22485 Cov.: 28 AF XY: 0.545 AC XY: 40269 AN XY: 73830

African (AFR) AF: 0.599 AC: 24641 AN: 41156

American (AMR) AF: 0.476 AC: 7241 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1504 AN: 3464

East Asian (EAS) AF: 0.551 AC: 2801 AN: 5082

South Asian (SAS) AF: 0.417 AC: 1996 AN: 4784

European-Finnish (FIN) AF: 0.656 AC: 6869 AN: 10466

Middle Eastern (MID) AF: 0.400 AC: 116 AN: 290

European-Non Finnish (NFE) AF: 0.521 AC: 35280 AN: 67774

Other (OTH) AF: 0.530 AC: 1115 AN: 2102

Alfa AF: 0.513 Hom.: 6545

Bravo AF: 0.536

TwinsUK AF: 0.536 AC: 1989

ALSPAC AF: 0.530 AC: 2043

ESP6500AA AF: 0.590 AC: 2600

ESP6500EA AF: 0.525 AC: 4515

ExAC AF: 0.523 AC: 63487

Asia WGS AF: 0.516 AC: 1791 AN: 3478

EpiCase AF: 0.505

EpiControl AF: 0.512

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 20, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Ectopia lentis 2, isolated, autosomal recessive Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Ectopia lentis et pupillae Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.035
DANN	Benign	0.67
DEOGEN2	Benign	0.00037	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-1.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.061
Sift	Benign	0.82	T
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.16
ClinPred		0.0029	T
GERP RS		-4.6
Varity_R		0.048
gMVP		0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41317515; hg19: chr1-150526044; COSMIC: COSV54997886; COSMIC: COSV54997886;