rs121918608

Variant names:

• chr20-34292375-T-C
• rs121918608
• NM_000687.4:c.428A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-34292375-T-C
• chr20-34292375-T-A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PP3_Moderate PP5_Very_Strong BS1_Supporting

The NM_000687.4(AHCY):​c.428A>G​(p.Tyr143Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: AHCY NM_000687.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.02
• Publications: 29 publications found

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]

AHCY Gene-Disease associations (from GenCC):

• hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 20-34292375-T-C is Pathogenic according to our data. Variant chr20-34292375-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000162 (236/1461002) while in subpopulation NFE AF = 0.000203 (226/1111978). AF 95% confidence interval is 0.000181. There are 0 homozygotes in GnomAdExome4. There are 111 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000687.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHCY	NM_000687.4	MANE Select	c.428A>G	p.Tyr143Cys	missense	Exon 4 of 10	NP_000678.1	A0A384MTQ3
	AHCY	NM_001322086.2		c.434A>G	p.Tyr145Cys	missense	Exon 4 of 10	NP_001309015.1
	AHCY	NM_001362750.2		c.428A>G	p.Tyr143Cys	missense	Exon 4 of 11	NP_001349679.1	A0A384MTQ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHCY	ENST00000217426.7	TSL:1 MANE Select	c.428A>G	p.Tyr143Cys	missense	Exon 4 of 10	ENSP00000217426.2	P23526-1
	AHCY	ENST00000538132.1	TSL:2	c.344A>G	p.Tyr115Cys	missense	Exon 4 of 10	ENSP00000442820.1	P23526-2
	AHCY	ENST00000468908.1	TSL:5	n.591A>G		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000797 AC: 20 AN: 250902 AF XY: 0.0000958

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000162 AC: 236 AN: 1461002 Hom.: 0 Cov.: 32 AF XY: 0.000153 AC XY: 111 AN XY: 726812

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.0000895 AC: 4 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5120

European-Non Finnish (NFE) AF: 0.000203 AC: 226 AN: 1111978

Other (OTH) AF: 0.0000829 AC: 5 AN: 60316

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000154 Hom.: 1

Bravo AF: 0.0000945

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (4)
3	-	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Rhabdomyolysis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.82
MPC		0.79
ClinPred		0.58	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.93
Mutation Taster		=4/96	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: rs121918608; hg19: chr20-32880181; COSMIC: COSV54154251; COSMIC: COSV54154251;