11-10455351-T-C

Variant names:

• chr11-10455351-T-C
• rs899011
• NM_001025389.2:c.-103T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001025389.2(AMPD3):​c.-103T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 985,192 control chromosomes in the GnomAD database, including 251,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (40178 hom., cov: 30)
  • Exomes 𝑓: 0.71 (211115 hom.)
• Consequence: AMPD3 NM_001025389.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.715
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-10455351-T-C is Benign according to our data. Variant chr11-10455351-T-C is described in ClinVar as [Benign]. Clinvar id is 302142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD3	NM_001025389.2	c.-103T>C		5_prime_UTR_variant	Exon 1 of 15	ENST00000396553.7	NP_001020560.1
AMPD3	NM_000480.3	c.22+4308T>C		intron_variant	Intron 1 of 14		NP_000471.1
AMPD3	NM_001172431.2	c.-278+4836T>C		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.-103T>C		5_prime_UTR_variant	Exon 1 of 15	1	NM_001025389.2	ENSP00000379801.2

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110298 AN: 151908 Hom.: 40159 Cov.: 30

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.743

Gnomad EAS AF: 0.771

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.725

GnomAD4 exome AF: 0.711 AC: 592526 AN: 833166 Hom.: 211115 Cov.: 49 AF XY: 0.711 AC XY: 273536 AN XY: 384754

African (AFR) AF: 0.724 AC: 11433 AN: 15786

American (AMR) AF: 0.784 AC: 771 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 3860 AN: 5152

East Asian (EAS) AF: 0.781 AC: 2835 AN: 3630

South Asian (SAS) AF: 0.596 AC: 9815 AN: 16460

European-Finnish (FIN) AF: 0.709 AC: 197 AN: 278

Middle Eastern (MID) AF: 0.734 AC: 1190 AN: 1622

European-Non Finnish (NFE) AF: 0.713 AC: 543244 AN: 761954

Other (OTH) AF: 0.703 AC: 19181 AN: 27300

GnomAD4 genome AF: 0.726 AC: 110364 AN: 152026 Hom.: 40178 Cov.: 30 AF XY: 0.724 AC XY: 53818 AN XY: 74314

African (AFR) AF: 0.725 AC: 30016 AN: 41426

American (AMR) AF: 0.774 AC: 11836 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.743 AC: 2577 AN: 3468

East Asian (EAS) AF: 0.771 AC: 3974 AN: 5152

South Asian (SAS) AF: 0.602 AC: 2903 AN: 4822

European-Finnish (FIN) AF: 0.717 AC: 7580 AN: 10572

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 48986 AN: 67976

Other (OTH) AF: 0.719 AC: 1522 AN: 2116

Alfa AF: 0.727 Hom.: 74096

Bravo AF: 0.735

Asia WGS AF: 0.638 AC: 2222 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Erythrocyte AMP deaminase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.4
DANN	Benign	0.81
PhyloP100		-0.71
PromoterAI		0.0082	Neutral
Mutation Taster		=298/2	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: rs899011; hg19: chr11-10476898;