rs13043752

Positions:

Variant summary

Our verdict is Benign. Variant got -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

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 links:

AHCY (HGNC:):

AHCY links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 471682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-34295502-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AHCY	NM_000687.4 linkuse as main transcript	c.112C>T	p.Arg38Trp	missense_variant	2/10	ENST00000217426.7	NP_000678.1	P23526-1A0A384MTQ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AHCY	ENST00000217426.7 linkuse as main transcript	c.112C>T	p.Arg38Trp	missense_variant	2/10	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

GnomAD3 exomes

AF:

0.0119

AC:

2959

AN:

249426

Hom.:

AF XY:

0.0118

AC XY:

1598

AN XY:

135208

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 SAS exome

AF:

0.00605

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

Gnomad4 AFR exome

AF:

0.00257

Gnomad4 AMR exome

AF:

0.00655

Gnomad4 ASJ exome

AF:

0.0207

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00589

Gnomad4 FIN exome

AF:

0.00955

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0112

GnomAD4 genome

AF:

0.0118

AC:

1790

AN:

152340

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

822

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00305

Gnomad4 AMR

AF:

0.00725

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00772

Gnomad4 NFE

AF:

0.0195

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0180

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

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over