9-133428649-C-G

Variant names:

• chr9-133428649-C-G
• NM_139027.6:c.702C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PP3_Strong

The NM_139027.6(ADAMTS13):​c.702C>G​(p.His234Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000833 in 1,200,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319

Genes affected

ADAMTS13 (HGNC:1366): (ADAM metallopeptidase with thrombospondin type 1 motif 13) This gene encodes a member of a family of proteins containing several distinct regions, including a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. The enzyme encoded by this gene specifically cleaves von Willebrand Factor (vWF). Defects in this gene are associated with thrombotic thrombocytopenic purpura. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_139027.6 (ADAMTS13) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a disulfide_bond (size 79) in uniprot entity ATS13_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_139027.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.702C>G	p.His234Gln	missense_variant	Exon 7 of 29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.702C>G	p.His234Gln	missense_variant	Exon 7 of 29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.33e-7 AC: 1 AN: 1200102 Hom.: 0 Cov.: 33 AF XY: 0.00000170 AC XY: 1 AN XY: 588392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;.;H;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;.;D;D
Vest4		0.86
MutPred		0.91		Loss of catalytic residue at H234 (P = 0.0788);Loss of catalytic residue at H234 (P = 0.0788);Loss of catalytic residue at H234 (P = 0.0788);Loss of catalytic residue at H234 (P = 0.0788);
MVP		0.96
MPC		1.1
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.56
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-136293769;