20-3227173-T-C

Variant names:

• chr20-3227173-T-C
• rs3810560
• NM_001324240.2:c.*485T>C

Variant summary

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

The NM_001324240.2(ITPA):​c.*485T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,246 control chromosomes in the GnomAD database, including 10,953 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 0.35 (10953 hom., cov: 34)
• Consequence: ITPA NM_001324240.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 11 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]

SLC4A11 (HGNC:16438): (solute carrier family 4 member 11) This gene encodes a voltage-regulated, electrogenic sodium-coupled borate cotransporter that is essential for borate homeostasis, cell growth and cell proliferation. Mutations in this gene have been associated with a number of endothelial corneal dystrophies including recessive corneal endothelial dystrophy 2, corneal dystrophy and perceptive deafness, and Fuchs endothelial corneal dystrophy. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

SLC4A11 Gene-Disease associations (from GenCC):

• corneal dystrophy, Fuchs endothelial, 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• congenital hereditary endothelial dystrophy of cornea

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• corneal dystrophy-perceptive deafness syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A11	NM_001174089.2	c.*614A>G		downstream_gene_variant		ENST00000642402.1	NP_001167560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A11	ENST00000642402.1	c.*614A>G		downstream_gene_variant			NM_001174089.2	ENSP00000493503.1
SLC4A11	ENST00000380056.7	c.*614A>G		downstream_gene_variant		1		ENSP00000369396.3
SLC4A11	ENST00000380059.7	c.*614A>G		downstream_gene_variant		2		ENSP00000369399.3

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52884 AN: 152128 Hom.: 10950 Cov.: 34

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.366

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.347 AC: 52892 AN: 152246 Hom.: 10953 Cov.: 34 AF XY: 0.353 AC XY: 26267 AN XY: 74424

African (AFR) AF: 0.119 AC: 4956 AN: 41566

American (AMR) AF: 0.383 AC: 5850 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1690 AN: 3472

East Asian (EAS) AF: 0.494 AC: 2557 AN: 5172

South Asian (SAS) AF: 0.651 AC: 3146 AN: 4830

European-Finnish (FIN) AF: 0.390 AC: 4126 AN: 10588

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29174 AN: 68018

Other (OTH) AF: 0.369 AC: 779 AN: 2112

Alfa AF: 0.421 Hom.: 10092

Bravo AF: 0.330

Asia WGS AF: 0.557 AC: 1936 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	1.8
DANN	Benign	0.80
PhyloP100		-1.2

Splicing

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

Other links and lift over

dbSNP: rs3810560; hg19: chr20-3207819;