19-8589243-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):ā€‹c.2157C>Gā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0042 ( 2 hom., cov: 31)
Exomes š‘“: 0.0057 ( 41 hom. )

Consequence

ADAMTS10
NM_030957.4 splice_region, synonymous

Scores

2
Splicing: ADA: 0.00009434
2

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]

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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
ADAMTS10NM_030957.4 linkc.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
ADAMTS10ENST00000597188.6 linkc.2157C>G p.Ala719Ala splice_region_variant, synonymous_variant 18/265 NM_030957.4 ENSP00000471851.1 A0A0A0MQW6

Frequencies

GnomAD3 genomes
AF:
0.00415
AC:
632
AN:
152110
Hom.:
2
Cov.:
31
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.:
5
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.:
41
Cov.:
33
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.:
2
Cov.:
31
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.:
0
Bravo
AF:
0.00411
Asia WGS
AF:
0.00115
AC:
4
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 submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsFeb 02, 2016- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024ADAMTS10: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Weill-Marchesani syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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.

Other links and lift over

dbSNP: rs150468696; hg19: chr19-8654127; API