NM_139027.6:c.695T>A

Variant names:

• chr9-133428642-T-A
• rs281875292
• NM_139027.6:c.695T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_139027.6(ADAMTS13):​c.695T>A​(p.Leu232Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000882 in 1,133,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: ADAMTS13 NM_139027.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.71
• Publications: 3 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_139027.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

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.695T>A	p.Leu232Gln	missense	Exon 7 of 29	NP_620596.2
	ADAMTS13	NM_139025.5		c.695T>A	p.Leu232Gln	missense	Exon 7 of 29	NP_620594.1
	ADAMTS13	NM_139026.6		c.695T>A	p.Leu232Gln	missense	Exon 7 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.695T>A	p.Leu232Gln	missense	Exon 7 of 29	ENSP00000347927.2
	ADAMTS13	ENST00000371929.7	TSL:1	c.695T>A	p.Leu232Gln	missense	Exon 7 of 29	ENSP00000360997.3
	ADAMTS13	ENST00000356589.6	TSL:1	c.695T>A	p.Leu232Gln	missense	Exon 7 of 29	ENSP00000348997.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 8.82e-7 AC: 1 AN: 1133584 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 553644

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22516

American (AMR) AF: 0.00 AC: 0 AN: 18358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17278

East Asian (EAS) AF: 0.00 AC: 0 AN: 19790

South Asian (SAS) AF: 0.00 AC: 0 AN: 52020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2966

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 936372

Other (OTH) AF: 0.00 AC: 0 AN: 43388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.94		Loss of stability (P = 0.0305)
MVP		0.93
MPC		1.0
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.65
gMVP		0.77
Mutation Taster		=3/97	disease causing

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

Other links and lift over

dbSNP: rs281875292; hg19: chr9-136293762;