11-10455429-C-T

Variant names:

• chr11-10455429-C-T
• rs576679601
• NM_001025389.2:c.-25C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001025389.2(AMPD3):​c.-25C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 972,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: AMPD3 NM_001025389.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.21
• Publications: 0 publications found

Genes affected

AMPD3 (HGNC:470): (adenosine monophosphate deaminase 3) This gene encodes a member of the AMP deaminase gene family. The encoded protein is a highly regulated enzyme that catalyzes the hydrolytic deamination of adenosine monophosphate to inosine monophosphate, a branch point in the adenylate catabolic pathway. This gene encodes the erythrocyte (E) isoforms, whereas other family members encode isoforms that predominate in muscle (M) and liver (L) cells. Mutations in this gene lead to the clinically asymptomatic, autosomal recessive condition erythrocyte AMP deaminase deficiency. Alternatively spliced transcript variants encoding different isoforms of this gene have been described. [provided by RefSeq, Jul 2008]

AMPD3 Gene-Disease associations (from GenCC):

• adenosine monophosphate deaminase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD3	NM_001025389.2	c.-25C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 15	ENST00000396553.7	NP_001020560.1
AMPD3	NM_001025389.2	c.-25C>T		5_prime_UTR_variant	Exon 1 of 15	ENST00000396553.7	NP_001020560.1
AMPD3	NM_000480.3	c.22+4386C>T		intron_variant	Intron 1 of 14		NP_000471.1
AMPD3	NM_001172431.2	c.-278+4914C>T		intron_variant	Intron 1 of 13		NP_001165902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMPD3	ENST00000396553.7	c.-25C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 15	1	NM_001025389.2	ENSP00000379801.2
AMPD3	ENST00000396553.7	c.-25C>T		5_prime_UTR_variant	Exon 1 of 15	1	NM_001025389.2	ENSP00000379801.2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 209 AN: 146880 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000470

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000488

GnomAD4 exome AF: 0.000101 AC: 83 AN: 825138 Hom.: 0 Cov.: 38 AF XY: 0.000110 AC XY: 42 AN XY: 381222

African (AFR) AF: 0.00364 AC: 57 AN: 15652

American (AMR) AF: 0.00 AC: 0 AN: 970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5098

East Asian (EAS) AF: 0.00 AC: 0 AN: 3604

South Asian (SAS) AF: 0.0000615 AC: 1 AN: 16268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 280

Middle Eastern (MID) AF: 0.000623 AC: 1 AN: 1604

European-Non Finnish (NFE) AF: 0.0000239 AC: 18 AN: 754618

Other (OTH) AF: 0.000222 AC: 6 AN: 27044

GnomAD4 genome AF: 0.00142 AC: 209 AN: 147040 Hom.: 1 Cov.: 31 AF XY: 0.00128 AC XY: 92 AN XY: 71764

African (AFR) AF: 0.00496 AC: 201 AN: 40528

American (AMR) AF: 0.000470 AC: 7 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 4638

South Asian (SAS) AF: 0.00 AC: 0 AN: 4290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66562

Other (OTH) AF: 0.000483 AC: 1 AN: 2072

Alfa AF: 0.000925 Hom.: 0

Bravo AF: 0.00151

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Erythrocyte AMP deaminase deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.92
PhyloP100		-1.2
PromoterAI		-0.026	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs576679601; hg19: chr11-10476976;