20-3209336-G-C

Variant names:

• chr20-3209336-G-C
• rs6139031
• NM_001424409.1:c.192+624G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001424409.1(ITPA):​c.192+624G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 484,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITPA NM_001424409.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.93
• Publications: 0 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

ENSG00000289494 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424409.1. 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
	ITPA	NM_001424409.1		c.192+624G>C		intron	N/A	NP_001411338.1
	ITPA	NM_001324237.2		c.-272+303G>C		intron	N/A	NP_001311166.1	Q8WWI0
	ITPA	NM_001324238.2		c.-275+303G>C		intron	N/A	NP_001311167.1	Q8WWI0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000289494	ENST00000690923.3		n.143C>G		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000289494	ENST00000795319.1		n.123C>G		non_coding_transcript_exon	Exon 1 of 2
	ITPA	ENST00000460676.5	TSL:3	n.136+303G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 1 AN: 484614 Hom.: 0 Cov.: 3 AF XY: 0.00000385 AC XY: 1 AN XY: 259736

African (AFR) AF: 0.00 AC: 0 AN: 13918

American (AMR) AF: 0.00 AC: 0 AN: 27880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15998

East Asian (EAS) AF: 0.00 AC: 0 AN: 30454

South Asian (SAS) AF: 0.00 AC: 0 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2104

European-Non Finnish (NFE) AF: 0.00000354 AC: 1 AN: 282374

Other (OTH) AF: 0.00 AC: 0 AN: 27132

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.27
DANN	Benign	0.49
PhyloP100		-2.9
PromoterAI		0.14	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6139031; hg19: chr20-3189982;