20-34280853-G-A

Variant names:

• chr20-34280853-G-A
• rs759056638
• NM_000687.4:c.*181C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000687.4(AHCY):​c.*181C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 907,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: AHCY NM_000687.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.827
• Publications: 0 publications found

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

ENSG00000250917 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000147 (111/754834) while in subpopulation MID AF = 0.00432 (13/3010). AF 95% confidence interval is 0.00255. There are 0 homozygotes in GnomAdExome4. There are 45 alleles in the male GnomAdExome4 subpopulation. Median coverage is 10. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHCY	NM_000687.4	c.*181C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000217426.7	NP_000678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHCY	ENST00000217426.7	c.*181C>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_000687.4	ENSP00000217426.2
AHCY	ENST00000480653.5	n.1628C>T		non_coding_transcript_exon_variant	Exon 9 of 9	2
AHCY	ENST00000538132.1	c.*181C>T		3_prime_UTR_variant	Exon 10 of 10	2		ENSP00000442820.1
ENSG00000250917	ENST00000512005.1	n.147+174C>T		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000147 AC: 111 AN: 754834 Hom.: 0 Cov.: 10 AF XY: 0.000117 AC XY: 45 AN XY: 385814

African (AFR) AF: 0.00 AC: 0 AN: 19064

American (AMR) AF: 0.000171 AC: 5 AN: 29208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17510

East Asian (EAS) AF: 0.00 AC: 0 AN: 31932

South Asian (SAS) AF: 0.000139 AC: 8 AN: 57734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30854

Middle Eastern (MID) AF: 0.00432 AC: 13 AN: 3010

European-Non Finnish (NFE) AF: 0.000132 AC: 70 AN: 529128

Other (OTH) AF: 0.000412 AC: 15 AN: 36394

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74458

African (AFR) AF: 0.0000722 AC: 3 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000170

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.60
PhyloP100		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs759056638; hg19: chr20-32868659;