20-34292375-T-A

Variant names:

• chr20-34292375-T-A
• NM_000687.4:c.428A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000687.4(AHCY):​c.428A>T​(p.Tyr143Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y143C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AHCY NM_000687.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02

Genes affected

AHCY (HGNC:343): (adenosylhomocysteinase) S-adenosylhomocysteine hydrolase belongs to the adenosylhomocysteinase family. It catalyzes the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to adenosine (Ado) and L-homocysteine (Hcy). Thus, it regulates the intracellular S-adenosylhomocysteine (SAH) concentration thought to be important for transmethylation reactions. Deficiency in this protein is one of the different causes of hypermethioninemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-34292375-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHCY	NM_000687.4	c.428A>T	p.Tyr143Phe	missense_variant	Exon 4 of 10	ENST00000217426.7	NP_000678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHCY	ENST00000217426.7	c.428A>T	p.Tyr143Phe	missense_variant	Exon 4 of 10	1	NM_000687.4	ENSP00000217426.2
AHCY	ENST00000538132.1	c.344A>T	p.Tyr115Phe	missense_variant	Exon 4 of 10	2		ENSP00000442820.1
AHCY	ENST00000468908.1	n.591A>T		non_coding_transcript_exon_variant	Exon 4 of 5	5
AHCY	ENST00000480653.5	n.475A>T		non_coding_transcript_exon_variant	Exon 4 of 9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461002 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726812

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.68	D;.
Eigen	Benign	0.068
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.46
Sift	Benign	0.14	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.0040	B;.
Vest4		0.59
MutPred		0.81		Gain of methylation at K142 (P = 0.0287);.;
MVP		0.75
MPC		0.44
ClinPred		0.73	D
GERP RS		5.0
Varity_R		0.59
gMVP		0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-32880181;