chr7-33014750-T-C

Variant names:

• chr7-33014750-T-C
• rs563703074
• NM_001002010.5:c.976A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001002010.5(NT5C3A):​c.976A>G​(p.Ile326Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: NT5C3A NM_001002010.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07
• Publications: 0 publications found

Genes affected

NT5C3A (HGNC:17820): (5'-nucleotidase, cytosolic IIIA) This gene encodes a member of the 5'-nucleotidase family of enzymes that catalyze the dephosphorylation of nucleoside 5'-monophosphates. The encoded protein is the type 1 isozyme of pyrimidine 5' nucleotidase and catalyzes the dephosphorylation of pyrimidine 5' monophosphates. Mutations in this gene are a cause of hemolytic anemia due to uridine 5-prime monophosphate hydrolase deficiency. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and pseudogenes of this gene are located on the long arm of chromosomes 3 and 4. [provided by RefSeq, Mar 2012]

NT5C3A Gene-Disease associations (from GenCC):

• hemolytic anemia due to pyrimidine 5' nucleotidase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30131572).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002010.5. 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
	NT5C3A	NM_001002010.5	MANE Select	c.976A>G	p.Ile326Val	missense	Exon 9 of 9	NP_001002010.2	X6RM59
	NT5C3A	NM_001374335.1		c.877A>G	p.Ile293Val	missense	Exon 8 of 8	NP_001361264.1
	NT5C3A	NM_001002009.3		c.874A>G	p.Ile292Val	missense	Exon 10 of 10	NP_001002009.1	Q9H0P0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NT5C3A	ENST00000610140.7	TSL:1 MANE Select	c.976A>G	p.Ile326Val	missense	Exon 9 of 9	ENSP00000476480.2	X6RM59
	NT5C3A	ENST00000456458.5	TSL:1	n.*881A>G		non_coding_transcript_exon	Exon 10 of 10	ENSP00000389676.2	F8WDR0
	NT5C3A	ENST00000456458.5	TSL:1	n.*881A>G		3_prime_UTR	Exon 10 of 10	ENSP00000389676.2	F8WDR0

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251000 AF XY: 0.00000737

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460244 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726446

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4924

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111696

Other (OTH) AF: 0.0000166 AC: 1 AN: 60252

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74484

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.048
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.34
Sift	Benign	0.051	T
Sift4G	Benign	0.10	T
Polyphen		0.011	B
Vest4		0.099
MutPred		0.73		Loss of catalytic residue at L336 (P = 0.0641)
MVP		0.78
MPC		0.20
ClinPred		0.30	T
GERP RS		5.9
Varity_R		0.31
gMVP		0.56
Mutation Taster		=75/25	polymorphism

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: rs563703074; hg19: chr7-33054362; COSMIC: COSV54240525; COSMIC: COSV54240525;