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. The variant received -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
• Publications: 0 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-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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL4	NM_019032.6	MANE Select	c.-84-300_-84-299dupAA		intron	N/A	NP_061905.2
	ADAMTSL4	NM_001288608.2		c.-84-300_-84-299dupAA		intron	N/A	NP_001275537.1	Q6UY14-3
	ADAMTSL4	NM_001378596.1		c.-84-300_-84-299dupAA		intron	N/A	NP_001365525.1	Q6UY14-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTSL4	ENST00000271643.9	TSL:5 MANE Select	c.-84-321_-84-320insAA		intron	N/A	ENSP00000271643.4	Q6UY14-1
	ADAMTSL4	ENST00000483335.1	TSL:1	n.1804_1805insAA		non_coding_transcript_exon	Exon 3 of 3
	ADAMTSL4	ENST00000369039.9	TSL:5	c.-84-321_-84-320insAA		intron	N/A	ENSP00000358035.5	Q6UY14-3

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

GnomAD2 exomes AF: 0.00211 AC: 8 AN: 3788 AF XY: 0.00198

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00517 AC: 4 AN: 774

American (AMR) AF: 0.000785 AC: 1 AN: 1274

Ashkenazi Jewish (ASJ) AF: 0.00213 AC: 2 AN: 938

East Asian (EAS) AF: 0.00131 AC: 2 AN: 1524

South Asian (SAS) AF: 0.000967 AC: 1 AN: 1034

European-Finnish (FIN) AF: 0.00155 AC: 2 AN: 1288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 476

European-Non Finnish (NFE) AF: 0.00154 AC: 26 AN: 16928

Other (OTH) AF: 0.000599 AC: 1 AN: 1670

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0133 AC: 353 AN: 26460

American (AMR) AF: 0.00163 AC: 14 AN: 8596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2324

East Asian (EAS) AF: 0.00 AC: 0 AN: 3292

South Asian (SAS) AF: 0.00 AC: 0 AN: 3034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4756

Middle Eastern (MID) AF: 0.00595 AC: 1 AN: 168

European-Non Finnish (NFE) AF: 0.000118 AC: 5 AN: 42364

Other (OTH) AF: 0.00250 AC: 3 AN: 1198

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.85

Splicing

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

Other links and lift over

dbSNP: rs199813152; hg19: chr1-150524367;