1-150558532-T-C

Variant names:

• chr1-150558532-T-C
• rs10888382
• NM_019032.6:c.2442T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_019032.6(ADAMTSL4):​c.2442T>C​(p.Asn814Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 1,613,790 control chromosomes in the GnomAD database, including 703,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58608 hom., cov: 33)
  • Exomes 𝑓: 0.94 (644548 hom.)
• Consequence: ADAMTSL4 NM_019032.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.94
• Publications: 20 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 Gene-Disease associations (from GenCC):

• ectopia lentis 2, isolated, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• ectopia lentis et pupillae

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-150558532-T-C is Benign according to our data. Variant chr1-150558532-T-C is described in ClinVar as Benign. ClinVar VariationId is 261076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.93 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.944 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.2442T>C	p.Asn814Asn	synonymous	Exon 15 of 19	NP_061905.2
	ADAMTSL4	NM_001288608.2		c.2511T>C	p.Asn837Asn	synonymous	Exon 16 of 20	NP_001275537.1
	ADAMTSL4	NM_001378596.1		c.2442T>C	p.Asn814Asn	synonymous	Exon 15 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.2442T>C	p.Asn814Asn	synonymous	Exon 15 of 19	ENSP00000271643.4
	ADAMTSL4	ENST00000369038.6	TSL:1	c.2442T>C	p.Asn814Asn	synonymous	Exon 13 of 17	ENSP00000358034.2
	ADAMTSL4	ENST00000369039.9	TSL:5	c.2511T>C	p.Asn837Asn	synonymous	Exon 16 of 20	ENSP00000358035.5

Frequencies

GnomAD3 genomes AF: 0.871 AC: 132483 AN: 152080 Hom.: 58597 Cov.: 33

Gnomad AFR AF: 0.702

Gnomad AMI AF: 0.917

Gnomad AMR AF: 0.893

Gnomad ASJ AF: 0.925

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.950

Gnomad OTH AF: 0.872

GnomAD2 exomes AF: 0.911 AC: 228846 AN: 251148 AF XY: 0.914

Gnomad AFR exome AF: 0.691

Gnomad AMR exome AF: 0.908

Gnomad ASJ exome AF: 0.923

Gnomad EAS exome AF: 0.847

Gnomad FIN exome AF: 0.980

Gnomad NFE exome AF: 0.949

Gnomad OTH exome AF: 0.920

GnomAD4 exome AF: 0.938 AC: 1370865 AN: 1461592 Hom.: 644548 Cov.: 100 AF XY: 0.937 AC XY: 681177 AN XY: 727122

African (AFR) AF: 0.695 AC: 23266 AN: 33480

American (AMR) AF: 0.907 AC: 40554 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 24170 AN: 26134

East Asian (EAS) AF: 0.891 AC: 35356 AN: 39700

South Asian (SAS) AF: 0.880 AC: 75869 AN: 86258

European-Finnish (FIN) AF: 0.978 AC: 51979 AN: 53138

Middle Eastern (MID) AF: 0.918 AC: 5296 AN: 5768

European-Non Finnish (NFE) AF: 0.952 AC: 1058861 AN: 1112000

Other (OTH) AF: 0.919 AC: 55514 AN: 60392

GnomAD4 genome AF: 0.871 AC: 132528 AN: 152198 Hom.: 58608 Cov.: 33 AF XY: 0.872 AC XY: 64860 AN XY: 74416

African (AFR) AF: 0.701 AC: 29063 AN: 41462

American (AMR) AF: 0.893 AC: 13658 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.925 AC: 3212 AN: 3472

East Asian (EAS) AF: 0.856 AC: 4423 AN: 5170

South Asian (SAS) AF: 0.868 AC: 4191 AN: 4826

European-Finnish (FIN) AF: 0.980 AC: 10411 AN: 10626

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.950 AC: 64615 AN: 68018

Other (OTH) AF: 0.873 AC: 1848 AN: 2116

Alfa AF: 0.880 Hom.: 105082

Bravo AF: 0.857

Asia WGS AF: 0.846 AC: 2942 AN: 3478

EpiCase AF: 0.946

EpiControl AF: 0.947

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Ectopia lentis et pupillae (2)
-	-	2	not provided (2)
-	-	1	Ectopia lentis 2, isolated, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.50
DANN	Benign	0.52
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs10888382; hg19: chr1-150531008; COSMIC: COSV55004231; COSMIC: COSV55004231;