rs201479827

chr20-34303236-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 338282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-34303236-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHCY	NM_000687.4	c.28+7C>T		splice_region_variant, intron_variant		ENST00000217426.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHCY	ENST00000217426.7	c.28+7C>T		splice_region_variant, intron_variant		1	NM_000687.4	P1
AHCY	ENST00000538132.1	c.-56-7651C>T		intron_variant		2
AHCY	ENST00000480653.5	n.75+7C>T		splice_region_variant, intron_variant, non_coding_transcript_variant		2
AHCY	ENST00000606061.1	n.115+7C>T		splice_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 588 AN: 152246 Hom.: 3 Cov.: 34

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

GnomAD3 exomes AF: 0.00388 AC: 604 AN: 155476 Hom.: 1 AF XY: 0.00381 AC XY: 312 AN XY: 81888

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 SAS exome AF: 0.000922

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.: 43 Cov.: 32 AF XY: 0.00540 AC XY: 3726 AN XY: 690082

Gnomad4 AFR exome AF: 0.000696

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.00358

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000972

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00478

GnomAD4 genome AF: 0.00386 AC: 588 AN: 152364 Hom.: 3 Cov.: 34 AF XY: 0.00413 AC XY: 308 AN XY: 74502

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00430 Hom.: 2

Bravo AF: 0.00305

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

AHCY: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.7
Dann	Benign	0.84

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

LitVar

Other links and lift over

dbSNP: rs201479827; hg19: chr20-32891042;