rs201479827

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.28+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,551,488 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0055 ( 43 hom. )

Consequence

AHCY
NM_000687.4 splice_region, intron

Scores

Splicing: ADA: 0.00008643

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.240

Publications

0 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 (BayesDel_noAF=-0.8).

BP6

Variant 20-34303236-G-A is Benign according to our data. Variant chr20-34303236-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 338282.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 = 0.00386 (588/152364) while in subpopulation NFE AF = 0.00526 (358/68030). AF 95% confidence interval is 0.00481. There are 3 homozygotes in GnomAd4. There are 308 alleles in the male GnomAd4 subpopulation. Median coverage is 34. 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.28+7C>T		splice_region_variant, intron_variant	Intron 1 of 9	ENST00000217426.7	NP_000678.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
AHCY	ENST00000217426.7 link	c.28+7C>T	splice_region_variant, intron_variant	Intron 1 of 9	1	NM_000687.4	ENSP00000217426.2
AHCY	ENST00000538132.1 link	c.-56-7651C>T	intron_variant	Intron 1 of 9	2		ENSP00000442820.1
AHCY	ENST00000480653.5 link	n.75+7C>T	splice_region_variant, intron_variant	Intron 1 of 8	2
AHCY	ENST00000606061.1 link	n.115+7C>T	splice_region_variant, intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00386

AC:

588

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000771

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00320

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00526

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00388

AC:

604

AN:

155476

AF XY:

0.00381

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.00259

Gnomad ASJ exome

AF:

0.00364

Gnomad EAS exome

AF:

0.0000884

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.00470

Gnomad OTH exome

AF:

0.00499

GnomAD4 exome

AF:

0.00554

AC:

7756

AN:

1399124

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

3726

AN XY:

690082

show subpopulations

African (AFR)

AF:

0.000696

AC:

AN:

31596

American (AMR)

AF:

0.00221

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00358

AC:

AN:

25174

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35736

South Asian (SAS)

AF:

0.000972

AC:

AN:

79192

European-Finnish (FIN)

AF:

0.0122

AC:

599

AN:

49170

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00612

AC:

6604

AN:

1078866

Other (OTH)

AF:

0.00478

AC:

277

AN:

57988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

443

886

1330

1773

2216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.00386

AC:

588

AN:

152364

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

308

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000769

AC:

AN:

41602

American (AMR)

AF:

0.00320

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0122

AC:

130

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00526

AC:

358

AN:

68030

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

130

163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00430

Hom.:

Bravo

AF:

0.00305

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AHCY: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

4.7

(source)

DANN

Benign

0.84

PhyloP100

-0.24

PromoterAI

-0.035

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000086

dbscSNV1_RF

Benign

0.0

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