chr19-8596459-T-C

Variant names:

• chr19-8596459-T-C
• rs7247944
• NM_030957.4:c.1085-47A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_030957.4(ADAMTS10):​c.1085-47A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,612,080 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0027 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: ADAMTS10 NM_030957.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 1 publications found

Genes affected

ADAMTS10 (HGNC:13201): (ADAM metallopeptidase with thrombospondin type 1 motif 10) This gene belongs to the ADAMTS (a disintegrin and metalloproteinase domain with thrombospondin type-1 motifs) family of zinc-dependent proteases. ADAMTS proteases are complex secreted enzymes containing a prometalloprotease domain of the reprolysin type attached to an ancillary domain with a highly conserved structure that includes at least one thrombospondin type 1 repeat. They have been demonstrated to have important roles in connective tissue organization, coagulation, inflammation, arthritis, angiogenesis and cell migration. The product of this gene plays a major role in growth and in skin, lens, and heart development. It is also a candidate gene for autosomal recessive Weill-Marchesani syndrome. [provided by RefSeq, Jul 2008]

ADAMTS10 Gene-Disease associations (from GenCC):

• Weill-Marchesani syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00273 (415/152208) while in subpopulation AFR AF = 0.00929 (386/41556). AF 95% confidence interval is 0.00852. There are 7 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030957.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS10	NM_030957.4	MANE Select	c.1085-47A>G		intron	N/A	NP_112219.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS10	ENST00000597188.6	TSL:5 MANE Select	c.1085-47A>G		intron	N/A	ENSP00000471851.1
	ADAMTS10	ENST00000270328.8	TSL:5	c.1085-47A>G		intron	N/A	ENSP00000270328.4
	ADAMTS10	ENST00000593913.5	TSL:5	n.*79-240A>G		intron	N/A	ENSP00000469901.1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152090 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000749 AC: 187 AN: 249816 AF XY: 0.000496

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000288 AC: 421 AN: 1459872 Hom.: 0 Cov.: 37 AF XY: 0.000233 AC XY: 169 AN XY: 726108

African (AFR) AF: 0.0101 AC: 337 AN: 33448

American (AMR) AF: 0.000649 AC: 29 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 38920

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111114

Other (OTH) AF: 0.000796 AC: 48 AN: 60288

GnomAD4 genome AF: 0.00273 AC: 415 AN: 152208 Hom.: 7 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74422

African (AFR) AF: 0.00929 AC: 386 AN: 41556

American (AMR) AF: 0.00131 AC: 20 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00155 Hom.: 1

Bravo AF: 0.00323

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.42
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs7247944; hg19: chr19-8661343;