NM_001368809.2:c.1407+3A>G

Variant names:

• chr1-109628498-A-G
• rs41280332
• NM_001368809.2:c.1407+3A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001368809.2(AMPD2):​c.1407+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,612,168 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 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 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (9 hom.)
• Consequence: AMPD2 NM_001368809.2 splice_region, intron
• Scores: Splicing: ADA: 0.0004856
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.304
• Publications: 2 publications found

Genes affected

AMPD2 (HGNC:469): (adenosine monophosphate deaminase 2) The protein encoded by this gene is important in purine metabolism by converting AMP to IMP. The encoded protein, which acts as a homotetramer, is one of three AMP deaminases found in mammals. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

AMPD2 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• hereditary spastic paraplegia 63

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000228703 (HGNC:40074):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-109628498-A-G is Benign according to our data. Variant chr1-109628498-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434144.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00296 (451/152148) while in subpopulation NFE AF = 0.0048 (326/67976). AF 95% confidence interval is 0.00437. There are 2 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMPD2	NM_001368809.2	c.1407+3A>G		splice_region_variant, intron_variant	Intron 12 of 18	ENST00000528667.7	NP_001355738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMPD2	ENST00000528667.7	c.1407+3A>G		splice_region_variant, intron_variant	Intron 12 of 18	1	NM_001368809.2	ENSP00000436541.2

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152030 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00480

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00267 AC: 666 AN: 249168 AF XY: 0.00271

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00400

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00401 AC: 5853 AN: 1460020 Hom.: 9 Cov.: 36 AF XY: 0.00388 AC XY: 2819 AN XY: 726404

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00104 AC: 90 AN: 86258

European-Finnish (FIN) AF: 0.00512 AC: 264 AN: 51610

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00470 AC: 5221 AN: 1111982

Other (OTH) AF: 0.00300 AC: 181 AN: 60374

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152148 Hom.: 2 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74404

African (AFR) AF: 0.000771 AC: 32 AN: 41506

American (AMR) AF: 0.00268 AC: 41 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4808

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00480 AC: 326 AN: 67976

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00365 Hom.: 0

Bravo AF: 0.00272

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AMPD2: BP4, BS2 -

Jul 30, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 28, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 63;C4014354:Pontocerebellar hypoplasia type 9 Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AMPD2-related disorder Benign:1

Apr 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.8
DANN	Benign	0.69
PhyloP100		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00049
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.050		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: rs41280332; hg19: chr1-110171120;