rs875989844

Variant names:

• chr1-109630343-C-G
• rs875989844
• NM_001368809.2:c.2094C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001368809.2(AMPD2):​c.2094C>G​(p.Tyr698*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: AMPD2 NM_001368809.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.31
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-109630343-C-G is Pathogenic according to our data. Variant chr1-109630343-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225763.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMPD2	NM_001368809.2	MANE Select	c.2094C>G	p.Tyr698*	stop_gained	Exon 17 of 19	NP_001355738.1
	AMPD2	NM_004037.9		c.2094C>G	p.Tyr698*	stop_gained	Exon 16 of 18	NP_004028.4
	AMPD2	NM_001308170.1		c.2031C>G	p.Tyr677*	stop_gained	Exon 15 of 17	NP_001295099.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMPD2	ENST00000528667.7	TSL:1 MANE Select	c.2094C>G	p.Tyr698*	stop_gained	Exon 17 of 19	ENSP00000436541.2
	AMPD2	ENST00000342115.8	TSL:1	c.2013C>G	p.Tyr671*	stop_gained	Exon 16 of 18	ENSP00000345498.4
	AMPD2	ENST00000526301.6	TSL:1	n.2157C>G		non_coding_transcript_exon	Exon 16 of 18

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pontocerebellar hypoplasia type 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		1.3
Vest4		0.93
ClinPred		1.0	D
GERP RS		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs875989844; hg19: chr1-110172965;