20-34295502-G-A

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.112C>T(p.Arg38Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,613,992 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 20 hom., cov: 32)

Exomes 𝑓: 0.015 ( 177 hom. )

Consequence

AHCY
NM_000687.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.64

Publications

26 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=0.010607451).

BP6

Variant 20-34295502-G-A is Benign according to our data. Variant chr20-34295502-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471682.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 = 0.0117 (1790/152340) while in subpopulation NFE AF = 0.0195 (1327/68028). AF 95% confidence interval is 0.0186. There are 20 homozygotes in GnomAd4. There are 822 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHCY	NM_000687.4 link	c.112C>T	p.Arg38Trp	missense_variant	Exon 2 of 10	ENST00000217426.7	NP_000678.1	P23526-1A0A384MTQ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHCY	ENST00000217426.7 link	c.112C>T	p.Arg38Trp	missense_variant	Exon 2 of 10	1	NM_000687.4	ENSP00000217426.2		P23526-1

Frequencies

GnomAD3 genomes

AF:

0.0118

AC:

1790

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00306

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0119

AC:

2959

AN:

249426

AF XY:

0.0118

show subpopulations

Gnomad AFR exome

AF:

0.00255

Gnomad AMR exome

AF:

0.00638

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00881

Gnomad NFE exome

AF:

0.0183

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0148

AC:

21632

AN:

1461652

Hom.:

177

Cov.:

AF XY:

0.0146

AC XY:

10600

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

33480

American (AMR)

AF:

0.00655

AC:

293

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

542

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00589

AC:

508

AN:

86246

European-Finnish (FIN)

AF:

0.00955

AC:

509

AN:

53280

Middle Eastern (MID)

AF:

0.0111

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0170

AC:

18954

AN:

1111968

Other (OTH)

AF:

0.0112

AC:

675

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1366

2732

4098

5464

6830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.0118

AC:

1790

AN:

152340

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

822

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00305

AC:

127

AN:

41572

American (AMR)

AF:

0.00725

AC:

111

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00290

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00772

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0195

AC:

1327

AN:

68028

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0172

Hom.:

Bravo

AF:

0.0111

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0201

AC:

173

ExAC

AF:

0.0116

AC:

1405

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0179

EpiControl

AF:

0.0188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Benign:4

Nov 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Benign

-0.051

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.9

M;.

PhyloP100

1.6

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.8

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.91

P;.

Vest4

0.15

MPC

0.98

ClinPred

0.056

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.73

Mutation Taster

=87/13

polymorphism

(source)

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

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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