rs75477151

chr1-150554089-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_019032.6(ADAMTSL4):c.1098G>A(p.Gly366=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,601,516 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (73 hom.)
• Consequence: ADAMTSL4 NM_019032.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0850

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-150554089-G-A is Benign according to our data. Variant chr1-150554089-G-A is described in ClinVar as [Benign]. Clinvar id is 261075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.085 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00488 (743/152252) while in subpopulation EAS AF= 0.0502 (259/5164). AF 95% confidence interval is 0.0451. There are 8 homozygotes in gnomad4. There are 415 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL4	NM_019032.6	c.1098G>A	p.Gly366=	synonymous_variant	6/19	ENST00000271643.9
ADAMTSL4-AS2	XR_001738229.2	n.210+1865C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTSL4	ENST00000271643.9	c.1098G>A	p.Gly366=	synonymous_variant	6/19	5	NM_019032.6	P1
ADAMTSL4-AS2	ENST00000442435.3	n.476+446C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 745 AN: 152134 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00903 AC: 2121 AN: 234856 Hom.: 39 AF XY: 0.00773 AC XY: 999 AN XY: 129272

Gnomad AFR exome AF: 0.000354

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.0535

Gnomad SAS exome AF: 0.00151

Gnomad FIN exome AF: 0.00885

Gnomad NFE exome AF: 0.000679

Gnomad OTH exome AF: 0.00559

GnomAD4 exome AF: 0.00279 AC: 4044 AN: 1449264 Hom.: 73 Cov.: 34 AF XY: 0.00265 AC XY: 1914 AN XY: 721324

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0254

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0467

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.00977

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00488 AC: 743 AN: 152252 Hom.: 8 Cov.: 31 AF XY: 0.00558 AC XY: 415 AN XY: 74422

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0502

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00951

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00216 Hom.: 2

Bravo AF: 0.00654

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ectopia lentis 2, isolated, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ectopia lentis et pupillae Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	13
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs75477151; hg19: chr1-150526565; COSMIC: COSV55006155; COSMIC: COSV55006155;