chr19-8580634-C-T

Variant names:

• chr19-8580634-C-T
• rs74498506
• NM_030957.4:c.*259G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030957.4(ADAMTS10):​c.*259G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 477,816 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (13 hom., cov: 31)
  • Exomes 𝑓: 0.00074 (4 hom.)
• Consequence: ADAMTS10 NM_030957.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0710
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 19-8580634-C-T is Benign according to our data. Variant chr19-8580634-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 893577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00678 (1025/151212) while in subpopulation AFR AF = 0.0236 (977/41402). AF 95% confidence interval is 0.0224. There are 13 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.*259G>A		3_prime_UTR	Exon 26 of 26	NP_112219.3	A0A0A0MQW6
	ADAMTS10	NM_001282352.2		c.*259G>A		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.*259G>A		3_prime_UTR	Exon 26 of 26	ENSP00000471851.1	A0A0A0MQW6
	ADAMTS10	ENST00000270328.8	TSL:5	c.*259G>A		3_prime_UTR	Exon 25 of 25	ENSP00000270328.4	A0A0A0MQW6
	ADAMTS10	ENST00000906412.1		c.*259G>A		3_prime_UTR	Exon 25 of 25	ENSP00000576471.1

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1020 AN: 151094 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00238

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000445

Gnomad OTH AF: 0.00432

GnomAD4 exome AF: 0.000744 AC: 243 AN: 326604 Hom.: 4 Cov.: 0 AF XY: 0.000658 AC XY: 115 AN XY: 174862

African (AFR) AF: 0.0207 AC: 190 AN: 9162

American (AMR) AF: 0.00166 AC: 24 AN: 14424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9512

East Asian (EAS) AF: 0.0000498 AC: 1 AN: 20096

South Asian (SAS) AF: 0.0000903 AC: 4 AN: 44298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17734

Middle Eastern (MID) AF: 0.000745 AC: 1 AN: 1342

European-Non Finnish (NFE) AF: 0.0000469 AC: 9 AN: 192006

Other (OTH) AF: 0.000776 AC: 14 AN: 18030

GnomAD4 genome AF: 0.00678 AC: 1025 AN: 151212 Hom.: 13 Cov.: 31 AF XY: 0.00674 AC XY: 498 AN XY: 73882

African (AFR) AF: 0.0236 AC: 977 AN: 41402

American (AMR) AF: 0.00238 AC: 36 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000445 AC: 3 AN: 67448

Other (OTH) AF: 0.00428 AC: 9 AN: 2104

Alfa AF: 0.00472 Hom.: 0

Bravo AF: 0.00788

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

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
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.90
PhyloP100		-0.071
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: rs74498506; hg19: chr19-8645518;