chr20-3209439-C-T

Variant names:

• chr20-3209439-C-T
• rs148477247
• ENST00000932180.1:c.-113C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001424409.1(ITPA):​c.192+727C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,043,096 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (42 hom.)
• Consequence: ITPA NM_001424409.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.148
• 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

ENSG00000289494 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-3209439-C-T is Benign according to our data. Variant chr20-3209439-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0564 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+727C>T		intron	N/A	NP_001411338.1
	ITPA	NM_001324237.2		c.-272+406C>T		intron	N/A	NP_001311166.1	Q8WWI0
	ITPA	NM_001324238.2		c.-275+406C>T		intron	N/A	NP_001311167.1	Q8WWI0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITPA	ENST00000932180.1		c.-113C>T		5_prime_UTR	Exon 1 of 6	ENSP00000602239.1
	ENSG00000289494	ENST00000690923.3		n.40G>A		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000289494	ENST00000795319.1		n.20G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2580 AN: 152138 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0129

GnomAD4 exome AF: 0.00169 AC: 1502 AN: 890842 Hom.: 42 Cov.: 12 AF XY: 0.00142 AC XY: 655 AN XY: 460424

African (AFR) AF: 0.0543 AC: 1191 AN: 21952

American (AMR) AF: 0.00294 AC: 104 AN: 35340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22000

East Asian (EAS) AF: 0.00 AC: 0 AN: 33714

South Asian (SAS) AF: 0.0000575 AC: 4 AN: 69546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48182

Middle Eastern (MID) AF: 0.00301 AC: 14 AN: 4650

European-Non Finnish (NFE) AF: 0.0000717 AC: 44 AN: 613800

Other (OTH) AF: 0.00348 AC: 145 AN: 41658

GnomAD4 genome AF: 0.0170 AC: 2581 AN: 152254 Hom.: 56 Cov.: 32 AF XY: 0.0163 AC XY: 1212 AN XY: 74430

African (AFR) AF: 0.0583 AC: 2424 AN: 41544

American (AMR) AF: 0.00746 AC: 114 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68020

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.00960 Hom.: 12

Bravo AF: 0.0195

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.85
PhyloP100		0.15
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs148477247; hg19: chr20-3190085;