rs10420313

Variant names:

• chr19-8586451-A-C
• rs10420313
• NM_030957.4:c.2423T>G

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.2423T>G​(p.Leu808Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,613,800 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (205 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (162 hom.)
• Consequence: ADAMTS10 NM_030957.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.31
• Publications: 7 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=0.003006488).
• BP6: Variant 19-8586451-A-C is Benign according to our data. Variant chr19-8586451-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0911 is higher than 0.05.

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.2423T>G	p.Leu808Arg	missense	Exon 21 of 26	NP_112219.3	A0A0A0MQW6
	ADAMTS10	NM_001282352.2		c.884T>G	p.Leu295Arg	missense	Exon 8 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.2423T>G	p.Leu808Arg	missense	Exon 21 of 26	ENSP00000471851.1	A0A0A0MQW6
	ADAMTS10	ENST00000270328.8	TSL:5	c.2423T>G	p.Leu808Arg	missense	Exon 20 of 25	ENSP00000270328.4	A0A0A0MQW6
	ADAMTS10	ENST00000906412.1		c.2423T>G	p.Leu808Arg	missense	Exon 20 of 25	ENSP00000576471.1

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4152 AN: 152176 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0936

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00744 AC: 1858 AN: 249630 AF XY: 0.00583

Gnomad AFR exome AF: 0.0941

Gnomad AMR exome AF: 0.00597

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000930

Gnomad NFE exome AF: 0.000905

Gnomad OTH exome AF: 0.00542

GnomAD4 exome AF: 0.00311 AC: 4540 AN: 1461506 Hom.: 162 Cov.: 32 AF XY: 0.00285 AC XY: 2075 AN XY: 727078

African (AFR) AF: 0.0943 AC: 3158 AN: 33480

American (AMR) AF: 0.00635 AC: 284 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86256

European-Finnish (FIN) AF: 0.0000753 AC: 4 AN: 53094

Middle Eastern (MID) AF: 0.0168 AC: 97 AN: 5768

European-Non Finnish (NFE) AF: 0.000450 AC: 500 AN: 1111992

Other (OTH) AF: 0.00717 AC: 433 AN: 60380

GnomAD4 genome AF: 0.0273 AC: 4160 AN: 152294 Hom.: 205 Cov.: 32 AF XY: 0.0267 AC XY: 1987 AN XY: 74456

African (AFR) AF: 0.0935 AC: 3886 AN: 41546

American (AMR) AF: 0.0121 AC: 185 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68014

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0102 Hom.: 181

Bravo AF: 0.0317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0883 AC: 389

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00881 AC: 1069

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.0052
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.3
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.080
Sift	Benign	0.087	T
Sift4G	Benign	0.061	T
Vest4		0.72
MVP		0.32
MPC		1.6
ClinPred		0.020	T
GERP RS		3.5
gMVP		0.82
Mutation Taster		=94/6	polymorphism (auto)

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: rs10420313; hg19: chr19-8651335;