chr20-3204477-A-G

Variant names:

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

Variant summary

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

The NM_023935.3(DDRGK1):​c.91+60T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,356,134 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: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: DDRGK1 NM_023935.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.922
• Publications: 0 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: 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=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDRGK1	NM_023935.3	c.91+60T>C		intron_variant	Intron 1 of 8	ENST00000354488.8	NP_076424.1
ITPA	NM_001424409.1	c.-126+198A>G		intron_variant	Intron 1 of 8		NP_001411338.1
ITPA	XM_047440139.1	c.-126+198A>G		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>C		intron_variant	Intron 1 of 8	1	NM_023935.3	ENSP00000346483.3
DDRGK1	ENST00000380201.2	c.91+60T>C		intron_variant	Intron 1 of 6	2		ENSP00000369548.2
ENSG00000303521	ENST00000795247.1	n.247+198A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000295 AC: 4 AN: 1356134 Hom.: 0 AF XY: 0.00000447 AC XY: 3 AN XY: 670638

African (AFR) AF: 0.00 AC: 0 AN: 30792

American (AMR) AF: 0.00 AC: 0 AN: 33986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24568

East Asian (EAS) AF: 0.00 AC: 0 AN: 35614

South Asian (SAS) AF: 0.0000383 AC: 3 AN: 78382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 9.46e-7 AC: 1 AN: 1056700

Other (OTH) AF: 0.00 AC: 0 AN: 56796

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.9
DANN	Benign	0.62
PhyloP100		-0.92
PromoterAI		-0.027	Neutral

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;