1-109621198-C-T

Position:

• chr1-109621198-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001368809.2(AMPD2):​c.23C>T​(p.Ser8Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S8C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AMPD2 NM_001368809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AMPD2. . Gene score misZ 2.8298 (greater than the threshold 3.09). Trascript score misZ 3.6281 (greater than threshold 3.09). GenCC has associacion of gene with pontocerebellar hypoplasia type 9, hereditary spastic paraplegia 63.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10045171).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMPD2	NM_001368809.2	c.23C>T	p.Ser8Phe	missense_variant	2/19	ENST00000528667.7
AMPD2	NM_004037.9	c.23C>T	p.Ser8Phe	missense_variant	1/18
AMPD2	NM_001308170.1	c.91C>T	p.Leu31=	synonymous_variant	1/17
AMPD2	NM_139156.4	c.10+920C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMPD2	ENST00000528667.7	c.23C>T	p.Ser8Phe	missense_variant	2/19	1	NM_001368809.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455936 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 723700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.070	B;B
Vest4		0.18
MutPred		0.24		Loss of glycosylation at S62 (P = 0.001);Loss of glycosylation at S62 (P = 0.001);
MVP		0.54
MPC		0.75
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.15
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs147463318; hg19: chr1-110163820;