19-8580807-GCC-GCCC

Variant names:

• chr19-8580807-G-GC
• rs576948646
• NM_030957.4:c.*85dupG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_030957.4(ADAMTS10):​c.*85dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,091,496 control chromosomes in the GnomAD database, including 12 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (12 hom.)
• Consequence: ADAMTS10 NM_030957.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.200
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00303 (460/151792) while in subpopulation NFE AF = 0.0054 (366/67824). AF 95% confidence interval is 0.00494. There are 0 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 12 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS10	NM_030957.4	MANE Select	c.*85dupG		3_prime_UTR	Exon 26 of 26	NP_112219.3	A0A0A0MQW6
	ADAMTS10	NM_001282352.2		c.*85dupG		3_prime_UTR	Exon 13 of 13	NP_001269281.1	Q9H324-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS10	ENST00000597188.6	TSL:5 MANE Select	c.*85dupG		3_prime_UTR	Exon 26 of 26	ENSP00000471851.1	A0A0A0MQW6
	ADAMTS10	ENST00000270328.8	TSL:5	c.*85dupG		3_prime_UTR	Exon 25 of 25	ENSP00000270328.4	A0A0A0MQW6
	ADAMTS10	ENST00000906412.1		c.*85dupG		3_prime_UTR	Exon 25 of 25	ENSP00000576471.1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 460 AN: 151676 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00530

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00540

Gnomad OTH AF: 0.000961

GnomAD4 exome AF: 0.00363 AC: 3414 AN: 939704 Hom.: 12 Cov.: 13 AF XY: 0.00346 AC XY: 1660 AN XY: 479570

African (AFR) AF: 0.000990 AC: 22 AN: 22212

American (AMR) AF: 0.000316 AC: 10 AN: 31680

Ashkenazi Jewish (ASJ) AF: 0.0000959 AC: 2 AN: 20852

East Asian (EAS) AF: 0.000121 AC: 4 AN: 33190

South Asian (SAS) AF: 0.000904 AC: 62 AN: 68564

European-Finnish (FIN) AF: 0.00495 AC: 179 AN: 36186

Middle Eastern (MID) AF: 0.00121 AC: 4 AN: 3294

European-Non Finnish (NFE) AF: 0.00446 AC: 3034 AN: 680988

Other (OTH) AF: 0.00227 AC: 97 AN: 42738

GnomAD4 genome AF: 0.00303 AC: 460 AN: 151792 Hom.: 0 Cov.: 31 AF XY: 0.00278 AC XY: 206 AN XY: 74176

African (AFR) AF: 0.000628 AC: 26 AN: 41416

American (AMR) AF: 0.000262 AC: 4 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4806

European-Finnish (FIN) AF: 0.00530 AC: 56 AN: 10560

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

European-Non Finnish (NFE) AF: 0.00540 AC: 366 AN: 67824

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.00298 Hom.: 0

Bravo AF: 0.00247

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
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: rs576948646; hg19: chr19-8645691;