chr9-133414782-G-T

Variant names:

• chr9-133414782-G-T
• rs374718488
• NM_020385.4:c.455C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020385.4(REXO4):​c.455C>A​(p.Thr152Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 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. T152I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: REXO4 NM_020385.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70
• Publications: 1 publications found

Genes affected

REXO4 (HGNC:12820): (REX4 homolog, 3'-5' exonuclease) Enables DNA binding activity and nuclease activity. Involved in DNA catabolic process, endonucleolytic; DNA catabolic process, exonucleolytic; and DNA repair. Located in nuclear speck and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071481496).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020385.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REXO4	NM_020385.4	MANE Select	c.455C>A	p.Thr152Lys	missense	Exon 2 of 8	NP_065118.2	Q9GZR2-1
	REXO4	NM_001279351.1		c.176C>A	p.Thr59Lys	missense	Exon 2 of 8	NP_001266280.1	Q9GZR2
	REXO4	NM_001279350.2		c.44C>A	p.Thr15Lys	missense	Exon 2 of 8	NP_001266279.1	B4E331

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REXO4	ENST00000371942.8	TSL:1 MANE Select	c.455C>A	p.Thr152Lys	missense	Exon 2 of 8	ENSP00000361010.3	Q9GZR2-1
	ADAMTS13	ENST00000485925.5	TSL:1	n.287+138G>T		intron	N/A
	REXO4	ENST00000903994.1		c.479C>A	p.Thr160Lys	missense	Exon 2 of 8	ENSP00000574053.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251464 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000188 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	0.00059	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.83
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
PROVEAN	Benign	0.16	N
REVEL	Benign	0.045
Sift	Uncertain	0.013	D
Sift4G	Benign	0.36	T
Polyphen		0.19	B
Vest4		0.53
MutPred		0.28		Gain of methylation at Q93 (P = 0.0225)
MVP		0.13
ClinPred		0.21	T
GERP RS		4.0
Varity_R		0.16
Mutation Taster		=98/2	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: rs374718488; hg19: chr9-136279902;