1-114684369-CAAAA-CAAA

Variant names:

• chr1-114684369-CA-C
• rs727503806
• NM_000036.3:c.382-6delT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000036.3(AMPD1):​c.382-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 889,366 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.062 (2 hom.)
• Consequence: AMPD1 NM_000036.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

Genes affected

AMPD1 (HGNC:468): (adenosine monophosphate deaminase 1) Adenosine monophosphate deaminase 1 catalyzes the deamination of AMP to IMP in skeletal muscle and plays an important role in the purine nucleotide cycle. Two other genes have been identified, AMPD2 and AMPD3, for the liver- and erythocyte-specific isoforms, respectively. Deficiency of the muscle-specific enzyme is apparently a common cause of exercise-induced myopathy and probably the most common cause of metabolic myopathy in the human. Alternatively spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Feb 2010]

AMPD1 Gene-Disease associations (from GenCC):

• myopathy due to myoadenylate deaminase deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• adenosine monophosphate deaminase deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 1-114684369-CA-C is Benign according to our data. Variant chr1-114684369-CA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166683.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD1	NM_000036.3	c.382-6delT		splice_region_variant, intron_variant	Intron 4 of 15	ENST00000520113.7	NP_000027.3
AMPD1	NM_001172626.2	c.370-6delT		splice_region_variant, intron_variant	Intron 3 of 14		NP_001166097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMPD1	ENST00000520113.7	c.382-6delT		splice_region_variant, intron_variant	Intron 4 of 15	1	NM_000036.3	ENSP00000430075.3

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 416 AN: 134166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00408

Gnomad ASJ AF: 0.00747

Gnomad EAS AF: 0.000422

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00428

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00389

GnomAD2 exomes AF: 0.158 AC: 11192 AN: 70624 AF XY: 0.163

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.0622 AC: 46962 AN: 755166 Hom.: 2 Cov.: 0 AF XY: 0.0623 AC XY: 23216 AN XY: 372814

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0660 AC: 1168 AN: 17690

American (AMR) AF: 0.0901 AC: 2170 AN: 24072

Ashkenazi Jewish (ASJ) AF: 0.0977 AC: 1263 AN: 12924

East Asian (EAS) AF: 0.0723 AC: 1440 AN: 19926

South Asian (SAS) AF: 0.0692 AC: 2908 AN: 42004

European-Finnish (FIN) AF: 0.0845 AC: 2449 AN: 28988

Middle Eastern (MID) AF: 0.0508 AC: 183 AN: 3604

European-Non Finnish (NFE) AF: 0.0577 AC: 33188 AN: 575086

Other (OTH) AF: 0.0710 AC: 2193 AN: 30872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00311 AC: 417 AN: 134200 Hom.: 1 Cov.: 32 AF XY: 0.00340 AC XY: 220 AN XY: 64742

African (AFR) AF: 0.00429 AC: 157 AN: 36602

American (AMR) AF: 0.00407 AC: 54 AN: 13258

Ashkenazi Jewish (ASJ) AF: 0.00747 AC: 24 AN: 3212

East Asian (EAS) AF: 0.000424 AC: 2 AN: 4718

South Asian (SAS) AF: 0.00 AC: 0 AN: 4192

European-Finnish (FIN) AF: 0.00428 AC: 33 AN: 7710

Middle Eastern (MID) AF: 0.0145 AC: 4 AN: 276

European-Non Finnish (NFE) AF: 0.00221 AC: 136 AN: 61600

Other (OTH) AF: 0.00386 AC: 7 AN: 1814

Alfa AF: 0.0914 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Muscle AMP deaminase deficiency Uncertain:1 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 18, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=97/3	polymorphism

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: rs727503806; hg19: chr1-115226990; COSMIC: COSV62415560;