chr9-133440431-G-T

Variant names:

• chr9-133440431-G-T
• rs36090624
• NM_139027.6:c.1874G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_139027.6(ADAMTS13):​c.1874G>T​(p.Arg625Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R625H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• congenital thrombotic thrombocytopenic purpura

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139027.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	NM_139027.6	MANE Select	c.1874G>T	p.Arg625Leu	missense	Exon 16 of 29	NP_620596.2
	ADAMTS13	NM_139025.5		c.1874G>T	p.Arg625Leu	missense	Exon 16 of 29	NP_620594.1
	ADAMTS13	NM_139026.6		c.1781G>T	p.Arg594Leu	missense	Exon 16 of 29	NP_620595.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS13	ENST00000355699.7	TSL:1 MANE Select	c.1874G>T	p.Arg625Leu	missense	Exon 16 of 29	ENSP00000347927.2
	ADAMTS13	ENST00000371929.7	TSL:1	c.1874G>T	p.Arg625Leu	missense	Exon 16 of 29	ENSP00000360997.3
	ADAMTS13	ENST00000356589.6	TSL:1	c.1781G>T	p.Arg594Leu	missense	Exon 16 of 29	ENSP00000348997.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.9
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.36
Sift	Benign	0.43	T
Sift4G	Benign	0.15	T
Polyphen		0.89	P
Vest4		0.59
MutPred		0.64		Loss of disorder (P = 0.0864)
MVP		0.82
MPC		0.67
ClinPred		0.71	D
GERP RS		4.1
Varity_R		0.23
gMVP		0.74
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs36090624; hg19: chr9-136305552;