20-3218536-C-G

Variant names:

• chr20-3218536-C-G
• rs114819623
• NM_033453.4:c.315C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001424408.1(ITPA):​c.315C>G​(p.Ala105Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A105A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITPA NM_001424408.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.96
• Publications: 1 publications found

Genes affected

ITPA (HGNC:6176): (inosine triphosphatase) This gene encodes an inosine triphosphate pyrophosphohydrolase. The encoded protein hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. This protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency which causes an accumulation of ITP in red blood cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ITPA Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 35

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• inosine triphosphatase deficiency

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP7: Synonymous conserved (PhyloP=-3.96 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424408.1. 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
	ITPA	NM_033453.4	MANE Select	c.315C>G	p.Ala105Ala	synonymous	Exon 6 of 8	NP_258412.1
	ITPA	NM_001424408.1		c.315C>G	p.Ala105Ala	synonymous	Exon 6 of 9	NP_001411337.1
	ITPA	NM_001424409.1		c.441C>G	p.Ala147Ala	synonymous	Exon 7 of 9	NP_001411338.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	ENST00000380113.8	TSL:1 MANE Select	c.315C>G	p.Ala105Ala	synonymous	Exon 6 of 8	ENSP00000369456.3
	ITPA	ENST00000455664.6	TSL:1	c.264C>G	p.Ala88Ala	synonymous	Exon 6 of 8	ENSP00000413282.1
	ITPA	ENST00000399838.3	TSL:1	c.192C>G	p.Ala64Ala	synonymous	Exon 4 of 6	ENSP00000382732.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.5
DANN	Benign	0.73
PhyloP100		-4.0

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: rs114819623; hg19: chr20-3199182;