chr9-133430025-A-T

Position:

• chr9-133430025-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_139027.6(ADAMTS13):​c.911A>T​(p.Tyr304Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y304C) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 30)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08

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]

ADAMTS13 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Disintegrin (size 96) in uniprot entity ATS13_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_139027.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-133430025-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS13	NM_139027.6	c.911A>T	p.Tyr304Phe	missense_variant	8/29	ENST00000355699.7	NP_620596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS13	ENST00000355699.7	c.911A>T	p.Tyr304Phe	missense_variant	8/29	1	NM_139027.6	ENSP00000347927.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.73
DEOGEN2	Benign	0.074	T;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N;.;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;.;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.28	B;.;B
Vest4		0.23
MutPred		0.49		Loss of phosphorylation at Y304 (P = 0.0264);.;Loss of phosphorylation at Y304 (P = 0.0264);
MVP		0.72
MPC		0.34
ClinPred		0.13	T
GERP RS		1.9
Varity_R		0.23
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs281875285; hg19: chr9-136295145;