rs41301825

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000687.4(AHCY):c.367G>A(p.Gly123Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00525 in 1,614,032 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 40 hom. )

Consequence

AHCY
NM_000687.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.11

Publications

17 publications found

Variant links:

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: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

AHCY links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0127850175).

BP6

Variant 20-34292436-C-T is Benign according to our data. Variant chr20-34292436-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 539061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00409 (623/152352) while in subpopulation NFE AF = 0.00732 (498/68016). AF 95% confidence interval is 0.00679. There are 3 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHCY	NM_000687.4 link	c.367G>A	p.Gly123Arg	missense_variant	Exon 4 of 10	ENST00000217426.7	NP_000678.1	P23526-1A0A384MTQ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AHCY	ENST00000217426.7 link	c.367G>A	p.Gly123Arg	missense_variant	Exon 4 of 10	1	NM_000687.4	ENSP00000217426.2	P23526-1
AHCY	ENST00000538132.1 link	c.283G>A	p.Gly95Arg	missense_variant	Exon 4 of 10	2		ENSP00000442820.1	P23526-2
AHCY	ENST00000468908.1 link	n.530G>A		non_coding_transcript_exon_variant	Exon 4 of 5	5
AHCY	ENST00000480653.5 link	n.414G>A		non_coding_transcript_exon_variant	Exon 4 of 9	2

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

623

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00732

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00382

AC:

961

AN:

251466

AF XY:

0.00382

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.00496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00631

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00537

AC:

7843

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00531

AC XY:

3858

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.000837

AC:

AN:

33472

American (AMR)

AF:

0.00331

AC:

148

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00463

AC:

121

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00121

AC:

104

AN:

86240

European-Finnish (FIN)

AF:

0.00114

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00214

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

0.00639

AC:

7103

AN:

1112006

Other (OTH)

AF:

0.00441

AC:

266

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

484

967

1451

1934

2418

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00409

AC:

623

AN:

152352

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41584

American (AMR)

AF:

0.00216

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00145

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00732

AC:

498

AN:

68016

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

108

144

180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00572

Hom.:

Bravo

AF:

0.00437

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00405

AC:

492

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00692

EpiControl

AF:

0.00693

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AHCY: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Benign:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

AHCY-related disorder

Benign:1

Nov 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Jul 04, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.077

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.0

M;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.5

D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.73

MutPred

0.56

Loss of catalytic residue at G123 (P = 0.0711);.;

MVP

0.74

MPC

1.4

ClinPred

0.026

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.54

gMVP

0.92

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over