19-8605046-C-G

Variant names:

• chr19-8605046-C-G
• rs7255721
• NM_030957.4:c.401G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030957.4(ADAMTS10):​c.401G>C​(p.Ser134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,609,244 control chromosomes in the GnomAD database, including 59,143 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3974 hom., cov: 32)
  • Exomes 𝑓: 0.26 (55169 hom.)
• Consequence: ADAMTS10 NM_030957.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.49
• Publications: 35 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004719436).
• BP6: Variant 19-8605046-C-G is Benign according to our data. Variant chr19-8605046-C-G is described in ClinVar as Benign. ClinVar VariationId is 769496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS10	NM_030957.4	c.401G>C	p.Ser134Thr	missense_variant	Exon 4 of 26	ENST00000597188.6	NP_112219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS10	ENST00000597188.6	c.401G>C	p.Ser134Thr	missense_variant	Exon 4 of 26	5	NM_030957.4	ENSP00000471851.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30497 AN: 152112 Hom.: 3976 Cov.: 32

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.0786

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.227

GnomAD4 exome AF: 0.263 AC: 382574 AN: 1457014 Hom.: 55169 Cov.: 36 AF XY: 0.258 AC XY: 187273 AN XY: 724530

African (AFR) AF: 0.0468 AC: 1562 AN: 33374

American (AMR) AF: 0.135 AC: 5960 AN: 44098

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4879 AN: 26026

East Asian (EAS) AF: 0.0284 AC: 1121 AN: 39450

South Asian (SAS) AF: 0.0820 AC: 7033 AN: 85732

European-Finnish (FIN) AF: 0.306 AC: 16026 AN: 52340

Middle Eastern (MID) AF: 0.221 AC: 1272 AN: 5762

European-Non Finnish (NFE) AF: 0.298 AC: 330299 AN: 1110088

Other (OTH) AF: 0.240 AC: 14422 AN: 60144

GnomAD4 genome AF: 0.200 AC: 30482 AN: 152230 Hom.: 3974 Cov.: 32 AF XY: 0.198 AC XY: 14734 AN XY: 74438

African (AFR) AF: 0.0560 AC: 2327 AN: 41566

American (AMR) AF: 0.187 AC: 2863 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 660 AN: 3470

East Asian (EAS) AF: 0.0282 AC: 146 AN: 5176

South Asian (SAS) AF: 0.0780 AC: 377 AN: 4832

European-Finnish (FIN) AF: 0.305 AC: 3236 AN: 10602

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19945 AN: 67982

Other (OTH) AF: 0.225 AC: 475 AN: 2108

Alfa AF: 0.259 Hom.: 1789

Bravo AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
LIST_S2	Benign	0.32	T;.
MetaRNN	Benign	0.0047	T;T
PhyloP100		1.5
Sift4G	Benign	0.62	T;T
Vest4		0.19
gMVP		0.67

Splicing

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

Other links and lift over

dbSNP: rs7255721; hg19: chr19-8669931;