20-3204477-A-T

Variant names:

• chr20-3204477-A-T
• rs11697186
• NM_023935.3:c.91+60T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_023935.3(DDRGK1):​c.91+60T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0774 in 1,507,878 control chromosomes in the GnomAD database, including 5,062 homozygotes. 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: 𝑓 0.071 (450 hom., cov: 32)
  • Exomes 𝑓: 0.078 (4612 hom.)
• Consequence: DDRGK1 NM_023935.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.922
• Publications: 32 publications found

Genes affected

DDRGK1 (HGNC:16110): (DDRGK domain containing 1) The protein encoded by this gene interacts with components of the ubiquitin fold modifier 1 conjugation pathway and helps prevent apoptosis in ER-stressed secretory tissues. In addition, the encoded protein regulates nuclear factor-κB activity. [provided by RefSeq, Dec 2015]

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

ENSG00000303521 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDRGK1	NM_023935.3	c.91+60T>A		intron_variant	Intron 1 of 8	ENST00000354488.8	NP_076424.1
ITPA	NM_001424409.1	c.-126+198A>T		intron_variant	Intron 1 of 8		NP_001411338.1
ITPA	XM_047440139.1	c.-126+198A>T		intron_variant	Intron 1 of 9		XP_047296095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDRGK1	ENST00000354488.8	c.91+60T>A		intron_variant	Intron 1 of 8	1	NM_023935.3	ENSP00000346483.3
DDRGK1	ENST00000380201.2	c.91+60T>A		intron_variant	Intron 1 of 6	2		ENSP00000369548.2
ENSG00000303521	ENST00000795247.1	n.247+198A>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0712 AC: 10834 AN: 152130 Hom.: 452 Cov.: 32

Gnomad AFR AF: 0.0662

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0394

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0728

Gnomad OTH AF: 0.0670

GnomAD4 exome AF: 0.0781 AC: 105864 AN: 1355630 Hom.: 4612 AF XY: 0.0797 AC XY: 53428 AN XY: 670410

African (AFR) AF: 0.0671 AC: 2067 AN: 30786

American (AMR) AF: 0.0326 AC: 1109 AN: 33978

Ashkenazi Jewish (ASJ) AF: 0.0725 AC: 1782 AN: 24566

East Asian (EAS) AF: 0.154 AC: 5490 AN: 35598

South Asian (SAS) AF: 0.131 AC: 10292 AN: 78362

European-Finnish (FIN) AF: 0.0596 AC: 2008 AN: 33704

Middle Eastern (MID) AF: 0.0641 AC: 358 AN: 5586

European-Non Finnish (NFE) AF: 0.0740 AC: 78162 AN: 1056274

Other (OTH) AF: 0.0809 AC: 4596 AN: 56776

GnomAD4 genome AF: 0.0712 AC: 10836 AN: 152248 Hom.: 450 Cov.: 32 AF XY: 0.0713 AC XY: 5310 AN XY: 74428

African (AFR) AF: 0.0661 AC: 2746 AN: 41564

American (AMR) AF: 0.0394 AC: 602 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3468

East Asian (EAS) AF: 0.175 AC: 904 AN: 5154

South Asian (SAS) AF: 0.135 AC: 653 AN: 4828

European-Finnish (FIN) AF: 0.0483 AC: 512 AN: 10610

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0728 AC: 4953 AN: 68014

Other (OTH) AF: 0.0658 AC: 139 AN: 2112

Alfa AF: 0.0763 Hom.: 306

Bravo AF: 0.0684

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.72
PhyloP100		-0.92
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs11697186; hg19: chr20-3185123; COSMIC: COSV107407629; COSMIC: COSV107407629;