1-150549837-C-T

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.-143C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 175,306 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: ADAMTSL4 NM_019032.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.849

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-150549837-C-T is Benign according to our data. Variant chr1-150549837-C-T is described in ClinVar as [Benign]. Clinvar id is 292513.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0121 (1846/152320) while in subpopulation AFR AF= 0.0423 (1757/41570). AF 95% confidence interval is 0.0406. There are 45 homozygotes in gnomad4. There are 863 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL4	NM_019032.6	c.-143C>T		5_prime_UTR_variant	2/19	ENST00000271643.9
ADAMTSL4-AS2	XR_001738229.2	n.211-1087G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTSL4	ENST00000271643.9	c.-143C>T		5_prime_UTR_variant	2/19	5	NM_019032.6	P1
ADAMTSL4-AS2	ENST00000442435.3	n.477-1087G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1834 AN: 152202 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00573

GnomAD4 exome AF: 0.00170 AC: 39 AN: 22986 Hom.: 0 Cov.: 0 AF XY: 0.00143 AC XY: 18 AN XY: 12586

Gnomad4 AFR exome AF: 0.0441

Gnomad4 AMR exome AF: 0.00189

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00285

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000233

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0121 AC: 1846 AN: 152320 Hom.: 45 Cov.: 33 AF XY: 0.0116 AC XY: 863 AN XY: 74482

Gnomad4 AFR AF: 0.0423

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.000601 Hom.: 0

Bravo AF: 0.0136

Asia WGS AF: 0.00375 AC: 13 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.9
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12061739; hg19: chr1-150522313;