chr1-109621129-G-GCCGGTGCCGCTCAGACTCCC

Position:

• chr1-109621129-G-GCCGGTGCCGCTCAGACTCCC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001368809.2(AMPD2):​c.-43_-24dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMPD2 NM_001368809.2 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-109621129-G-GCCGGTGCCGCTCAGACTCCC is Pathogenic according to our data. Variant chr1-109621129-G-GCCGGTGCCGCTCAGACTCCC is described in ClinVar as [Pathogenic]. Clinvar id is 1991577.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMPD2	NM_001368809.2	c.-43_-24dup		5_prime_UTR_variant	2/19	ENST00000528667.7	NP_001355738.1
AMPD2	NM_001308170.1	c.26_45dup	p.Leu16ValfsTer32	frameshift_variant	1/17		NP_001295099.1
AMPD2	NM_139156.4	c.10+855_10+874dup		intron_variant			NP_631895.1
AMPD2	NM_004037.9			upstream_gene_variant			NP_004028.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMPD2	ENST00000528667.7	c.-43_-24dup		5_prime_UTR_variant	2/19	1	NM_001368809.2	ENSP00000436541	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 19, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with AMPD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala47Glyfs*147) in the AMPD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AMPD2 are known to be pathogenic (PMID: 23911318). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-110163751;