chr19-8586451-A-C

Position:

• chr19-8586451-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 12/18 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

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADAMTS10. . Gene score misZ 3.628 (greater than the threshold 3.09). Trascript score misZ 3.793 (greater than threshold 3.09). GenCC has associacion of gene with Weill-Marchesani syndrome 1, Weill-Marchesani syndrome.
• 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 [Likely_benign]. Clinvar id is 330585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8586451-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS10	NM_030957.4	c.2423T>G	p.Leu808Arg	missense_variant	21/26	ENST00000597188.6	NP_112219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS10	ENST00000597188.6	c.2423T>G	p.Leu808Arg	missense_variant	21/26	5	NM_030957.4	ENSP00000471851.1

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

GnomAD3 exomes AF: 0.00744 AC: 1858 AN: 249630 Hom.: 59 AF XY: 0.00583 AC XY: 789 AN XY: 135280

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 SAS exome AF: 0.000163

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

Gnomad4 AFR exome AF: 0.0943

Gnomad4 AMR exome AF: 0.00635

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000753

Gnomad4 NFE exome AF: 0.000450

Gnomad4 OTH exome AF: 0.00717

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

Gnomad4 AFR AF: 0.0935

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00645 Hom.: 57

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	- -

Weill-Marchesani syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 15, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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;T;.
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.2	.;N;.
REVEL	Benign	0.080
Sift	Benign	0.087	.;T;.
Sift4G	Benign	0.061	T;T;T
Vest4		0.72
MVP		0.32
MPC		1.6
ClinPred		0.020	T
GERP RS		3.5
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs10420313; hg19: chr19-8651335;