20-34280733-A-C

Variant names:

• chr20-34280733-A-C
• rs13245
• NM_000687.4:c.*301T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000687.4(AHCY):​c.*301T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 445,170 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: AHCY NM_000687.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0890
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-34280733-A-C is Benign according to our data. Variant chr20-34280733-A-C is described in ClinVar as [Benign]. Clinvar id is 338267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1714/152276) while in subpopulation AFR AF = 0.0381 (1584/41556). AF 95% confidence interval is 0.0366. There are 32 homozygotes in GnomAd4. There are 793 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHCY	NM_000687.4	c.*301T>G		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.*301T>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_000687.4	ENSP00000217426.2
AHCY	ENST00000480653.5	n.1748T>G		non_coding_transcript_exon_variant	Exon 9 of 9	2
AHCY	ENST00000538132.1	c.*301T>G		3_prime_UTR_variant	Exon 10 of 10	2		ENSP00000442820.1
ENSG00000250917	ENST00000512005.1	n.147+294T>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1672 AN: 152158 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00150 AC: 440 AN: 292894 Hom.: 5 Cov.: 2 AF XY: 0.00128 AC XY: 200 AN XY: 156334

African (AFR) AF: 0.0347 AC: 293 AN: 8450

American (AMR) AF: 0.00350 AC: 48 AN: 13724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8376

East Asian (EAS) AF: 0.00 AC: 0 AN: 16104

South Asian (SAS) AF: 0.000210 AC: 9 AN: 42934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15580

Middle Eastern (MID) AF: 0.00248 AC: 3 AN: 1212

European-Non Finnish (NFE) AF: 0.000188 AC: 32 AN: 170398

Other (OTH) AF: 0.00341 AC: 55 AN: 16116

GnomAD4 genome AF: 0.0113 AC: 1714 AN: 152276 Hom.: 32 Cov.: 32 AF XY: 0.0107 AC XY: 793 AN XY: 74456

African (AFR) AF: 0.0381 AC: 1584 AN: 41556

American (AMR) AF: 0.00562 AC: 86 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68024

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00815 Hom.: 2

Bravo AF: 0.0131

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.60
PhyloP100		0.089
Mutation Taster		=100/0	polymorphism

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: rs13245; hg19: chr20-32868539;