rs57344541

chr20-34303304-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000687.4(AHCY):c.-34C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,551,714 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0079 (11 hom., cov: 34)
  • Exomes 𝑓: 0.011 (81 hom.)
• Consequence: AHCY NM_000687.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.564

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 20-34303304-G-A is Benign according to our data. Variant chr20-34303304-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218468.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00795 (1211/152362) while in subpopulation NFE AF= 0.0127 (864/68030). AF 95% confidence interval is 0.012. There are 11 homozygotes in gnomad4. There are 589 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AHCY	NM_000687.4	c.-34C>T		5_prime_UTR_variant	1/10	ENST00000217426.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AHCY	ENST00000217426.7	c.-34C>T		5_prime_UTR_variant	1/10	1	NM_000687.4	P1
AHCY	ENST00000538132.1	c.-56-7719C>T		intron_variant		2
AHCY	ENST00000480653.5	n.14C>T		non_coding_transcript_exon_variant	1/9	2
AHCY	ENST00000606061.1	n.54C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00795 AC: 1211 AN: 152244 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.00190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00771 AC: 1205 AN: 156280 Hom.: 7 AF XY: 0.00782 AC XY: 644 AN XY: 82310

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.00856

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00184

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00747

GnomAD4 exome AF: 0.0109 AC: 15209 AN: 1399352 Hom.: 81 Cov.: 32 AF XY: 0.0107 AC XY: 7391 AN XY: 690196

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.00914

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00196

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.00991

GnomAD4 genome AF: 0.00795 AC: 1211 AN: 152362 Hom.: 11 Cov.: 34 AF XY: 0.00791 AC XY: 589 AN XY: 74500

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0113 Hom.: 3

Bravo AF: 0.00686

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2022	- -
Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	11
Dann	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Other links and lift over

dbSNP: rs57344541; hg19: chr20-32891110;