20-3209336-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001424409.1(ITPA):​c.192+624G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 636,140 control chromosomes in the GnomAD database, including 15,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3297 hom., cov: 31)
  • Exomes 𝑓: 0.22 (12314 hom.)
• Consequence: ITPA NM_001424409.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.93
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 20-3209336-G-A is Benign according to our data. Variant chr20-3209336-G-A is described in ClinVar as Benign. ClinVar VariationId is 1235259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

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>A		intron	N/A	NP_001411338.1
	ITPA	NM_001324237.2		c.-272+303G>A		intron	N/A	NP_001311166.1	Q8WWI0
	ITPA	NM_001324238.2		c.-275+303G>A		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>T		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000289494	ENST00000795319.1		n.123C>T		non_coding_transcript_exon	Exon 1 of 2
	ITPA	ENST00000460676.5	TSL:3	n.136+303G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31009 AN: 151948 Hom.: 3298 Cov.: 31

Gnomad AFR AF: 0.164

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.220 AC: 106255 AN: 484074 Hom.: 12314 Cov.: 3 AF XY: 0.221 AC XY: 57217 AN XY: 259454

African (AFR) AF: 0.166 AC: 2303 AN: 13908

American (AMR) AF: 0.127 AC: 3526 AN: 27868

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 3929 AN: 15972

East Asian (EAS) AF: 0.155 AC: 4722 AN: 30440

South Asian (SAS) AF: 0.215 AC: 11646 AN: 54116

European-Finnish (FIN) AF: 0.244 AC: 7470 AN: 30572

Middle Eastern (MID) AF: 0.197 AC: 414 AN: 2100

European-Non Finnish (NFE) AF: 0.235 AC: 66348 AN: 282008

Other (OTH) AF: 0.218 AC: 5897 AN: 27090

GnomAD4 genome AF: 0.204 AC: 31020 AN: 152066 Hom.: 3297 Cov.: 31 AF XY: 0.203 AC XY: 15079 AN XY: 74324

African (AFR) AF: 0.163 AC: 6782 AN: 41492

American (AMR) AF: 0.156 AC: 2379 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 801 AN: 3470

East Asian (EAS) AF: 0.180 AC: 923 AN: 5140

South Asian (SAS) AF: 0.207 AC: 999 AN: 4818

European-Finnish (FIN) AF: 0.228 AC: 2411 AN: 10572

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16047 AN: 67974

Other (OTH) AF: 0.196 AC: 414 AN: 2110

Alfa AF: 0.222 Hom.: 944

Bravo AF: 0.193

Asia WGS AF: 0.151 AC: 525 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.34
DANN	Benign	0.79
PhyloP100		-2.9
PromoterAI		-0.0065	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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;