11-10455142-A-G

Variant names:

• chr11-10455142-A-G
• rs899013
• ENST00000396554.7:c.22+4099A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_000480.3(AMPD3):​c.22+4099A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 984,754 control chromosomes in the GnomAD database, including 175,912 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.60 (27711 hom., cov: 31)
  • Exomes 𝑓: 0.60 (148201 hom.)
• Consequence: AMPD3 NM_000480.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 11-10455142-A-G is Benign according to our data. Variant chr11-10455142-A-G is described in ClinVar as [Benign]. Clinvar id is 302137.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD3	NM_000480.3	c.22+4099A>G		intron_variant	Intron 1 of 14		NP_000471.1
AMPD3	NM_001172431.2	c.-278+4627A>G		intron_variant	Intron 1 of 13		NP_001165902.1
AMPD3	NM_001025389.2	c.-312A>G		upstream_gene_variant		ENST00000396553.7	NP_001020560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMPD3	ENST00000396553.7	c.-312A>G		upstream_gene_variant		1	NM_001025389.2	ENSP00000379801.2

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91252 AN: 151780 Hom.: 27699 Cov.: 31

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.786

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.616

GnomAD4 exome AF: 0.596 AC: 496036 AN: 832856 Hom.: 148201 Cov.: 30 AF XY: 0.596 AC XY: 229207 AN XY: 384606

African (AFR) AF: 0.552 AC: 8708 AN: 15776

American (AMR) AF: 0.726 AC: 714 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 3385 AN: 5148

East Asian (EAS) AF: 0.779 AC: 2829 AN: 3630

South Asian (SAS) AF: 0.509 AC: 8383 AN: 16460

European-Finnish (FIN) AF: 0.562 AC: 155 AN: 276

Middle Eastern (MID) AF: 0.647 AC: 1048 AN: 1620

European-Non Finnish (NFE) AF: 0.597 AC: 454584 AN: 761674

Other (OTH) AF: 0.595 AC: 16230 AN: 27288

GnomAD4 genome AF: 0.601 AC: 91307 AN: 151898 Hom.: 27711 Cov.: 31 AF XY: 0.601 AC XY: 44613 AN XY: 74242

African (AFR) AF: 0.560 AC: 23179 AN: 41410

American (AMR) AF: 0.676 AC: 10317 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2223 AN: 3472

East Asian (EAS) AF: 0.770 AC: 3970 AN: 5154

South Asian (SAS) AF: 0.524 AC: 2525 AN: 4818

European-Finnish (FIN) AF: 0.562 AC: 5912 AN: 10526

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 40999 AN: 67948

Other (OTH) AF: 0.609 AC: 1284 AN: 2108

Alfa AF: 0.593 Hom.: 6055

Bravo AF: 0.612

Asia WGS AF: 0.573 AC: 1996 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Erythrocyte AMP deaminase deficiency Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.78
PhyloP100		1.1
PromoterAI		-0.0070	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs899013; hg19: chr11-10476689;