1-150560832-C-A

Position:

• chr1-150560832-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_019032.6(ADAMTSL4):​c.*636C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 158,430 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (58 hom., cov: 32)
  • Exomes 𝑓: 0.020 (1 hom.)
• Consequence: ADAMTSL4 NM_019032.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.461

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-AS1 (HGNC:32041): (ADAMTSL4 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-150560832-C-A is Benign according to our data. Variant chr1-150560832-C-A is described in ClinVar as [Benign]. Clinvar id is 292576.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0211 (3208/152284) while in subpopulation NFE AF= 0.0339 (2309/68014). AF 95% confidence interval is 0.0328. There are 58 homozygotes in gnomad4. There are 1486 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTSL4	NM_019032.6	c.*636C>A		3_prime_UTR_variant	19/19	ENST00000271643.9	NP_061905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTSL4	ENST00000271643.9	c.*636C>A		3_prime_UTR_variant	19/19	5	NM_019032.6	ENSP00000271643	P1
ADAMTSL4-AS1	ENST00000615012.1	n.1284G>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3210 AN: 152166 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00874

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00747

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.0143

GnomAD4 exome AF: 0.0203 AC: 125 AN: 6146 Hom.: 1 Cov.: 0 AF XY: 0.0190 AC XY: 67 AN XY: 3526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00563

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00917

Gnomad4 FIN exome AF: 0.0326

Gnomad4 NFE exome AF: 0.0313

Gnomad4 OTH exome AF: 0.0208

GnomAD4 genome AF: 0.0211 AC: 3208 AN: 152284 Hom.: 58 Cov.: 32 AF XY: 0.0200 AC XY: 1486 AN XY: 74464

Gnomad4 AFR AF: 0.00871

Gnomad4 AMR AF: 0.00882

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.0339

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0290 Hom.: 7

Bravo AF: 0.0195

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.40
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs35531650; hg19: chr1-150533308;