1-150551891-CAAAAAAA-CAAAAAAAAA

Variant names:

• chr1-150551891-C-CAA
• rs199813152
• NM_019032.6:c.-84-300_-84-299dupAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_019032.6(ADAMTSL4):​c.-84-300_-84-299dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 118,620 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: ADAMTSL4 NM_019032.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.855

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)

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00406 (376/92714) while in subpopulation AFR AF= 0.0133 (353/26460). AF 95% confidence interval is 0.0122. There are 3 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTSL4	NM_019032.6	c.-84-300_-84-299dupAA		intron_variant	Intron 2 of 18	ENST00000271643.9	NP_061905.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTSL4	ENST00000271643.9	c.-84-321_-84-320insAA		intron_variant	Intron 2 of 18	5	NM_019032.6	ENSP00000271643.4

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 375 AN: 92694 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00556

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00253

GnomAD3 exomes AF: 0.00211 AC: 8 AN: 3788 Hom.: 0 AF XY: 0.00198 AC XY: 4 AN XY: 2022

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.00667

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00151 AC: 39 AN: 25906 Hom.: 0 Cov.: 0 AF XY: 0.00150 AC XY: 20 AN XY: 13334

Gnomad4 AFR exome AF: 0.00517

Gnomad4 AMR exome AF: 0.000785

Gnomad4 ASJ exome AF: 0.00213

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.000967

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00154

Gnomad4 OTH exome AF: 0.000599

GnomAD4 genome AF: 0.00406 AC: 376 AN: 92714 Hom.: 3 Cov.: 30 AF XY: 0.00391 AC XY: 171 AN XY: 43726

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00250

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199813152; hg19: chr1-150524367;