1-150551992-G-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.-84-213G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 473,812 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (39 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: ADAMTSL4 NM_019032.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.530

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]

MIR4257 (HGNC:38312): (microRNA 4257) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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=-0.73).
• BP6: Variant 1-150551992-G-A is Benign according to our data. Variant chr1-150551992-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1200909.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1663/152264) while in subpopulation AFR AF= 0.0387 (1609/41526). AF 95% confidence interval is 0.0372. There are 39 homozygotes in gnomad4. There are 778 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTSL4	NM_019032.6	c.-84-213G>A		intron_variant		ENST00000271643.9
MIR4257	NR_036211.1	n.64G>A		non_coding_transcript_exon_variant	1/1
ADAMTSL4-AS2	XR_001738229.2	n.211-3242C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTSL4	ENST00000271643.9	c.-84-213G>A		intron_variant		5	NM_019032.6	P1
MIR4257	ENST00000581735.1	n.64G>A		mature_miRNA_variant	1/1
ADAMTSL4-AS2	ENST00000442435.3	n.476+2543C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1655 AN: 152148 Hom.: 39 Cov.: 31

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00290 AC: 101 AN: 34834 Hom.: 1 AF XY: 0.00177 AC XY: 32 AN XY: 18100

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.000900

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000273

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00144 AC: 462 AN: 321548 Hom.: 9 Cov.: 0 AF XY: 0.00120 AC XY: 199 AN XY: 166026

Gnomad4 AFR exome AF: 0.0374

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000154

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000403

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.0109 AC: 1663 AN: 152264 Hom.: 39 Cov.: 31 AF XY: 0.0105 AC XY: 778 AN XY: 74438

Gnomad4 AFR AF: 0.0387

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00481 Hom.: 5

Bravo AF: 0.0124

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	7.5
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs74743733; hg19: chr1-150524468;