19-8589243-G-C

Position:

chr19-8589243-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_030957.4(ADAMTS10):c.2157C>G(p.Ala719Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,612,584 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0057 ( 41 hom. )

Consequence

ADAMTS10
NM_030957.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00009434

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.26

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 19-8589243-G-C is Benign according to our data. Variant chr19-8589243-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 235214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8589243-G-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.26 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00415 (632/152228) while in subpopulation NFE AF= 0.00688 (468/67998). AF 95% confidence interval is 0.00637. There are 2 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS10	NM_030957.4 link	c.2157C>G	p.Ala719Ala	splice_region_variant, synonymous_variant	18/26	ENST00000597188.6	NP_112219.3	Q9H324A0A0A0MQW6Q6ZN14Q59FE5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS10	ENST00000597188.6 link	c.2157C>G	p.Ala719Ala	splice_region_variant, synonymous_variant	18/26	5	NM_030957.4	ENSP00000471851.1		A0A0A0MQW6

Frequencies

GnomAD3 genomes

AF:

0.00415

AC:

632

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.00341

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00688

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00434

AC:

1075

AN:

247862

Hom.:

AF XY:

0.00425

AC XY:

573

AN XY:

134788

show subpopulations

Gnomad AFR exome

AF:

0.000872

Gnomad AMR exome

AF:

0.00371

Gnomad ASJ exome

AF:

0.00469

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.00233

Gnomad NFE exome

AF:

0.00678

Gnomad OTH exome

AF:

0.00346

GnomAD4 exome

AF:

0.00572

AC:

8348

AN:

1460356

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

4177

AN XY:

726570

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00382

Gnomad4 ASJ exome

AF:

0.00432

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00181

Gnomad4 FIN exome

AF:

0.00246

Gnomad4 NFE exome

AF:

0.00675

Gnomad4 OTH exome

AF:

0.00406

GnomAD4 genome

AF:

0.00415

AC:

632

AN:

152228

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.00688

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00381

Hom.:

Bravo

AF:

0.00411

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00551

EpiControl

AF:

0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 02, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ADAMTS10: BP4, BP7, BS2 -
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	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Weill-Marchesani syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.0050

DANN

Benign

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000094

dbscSNV1_RF

Benign

0.020

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over