NM_000687.4:c.*301T>G

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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

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 VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000687.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHCY	NM_000687.4	MANE Select	c.*301T>G		3_prime_UTR	Exon 10 of 10	NP_000678.1	A0A384MTQ3
	AHCY	NM_001322086.2		c.*301T>G		3_prime_UTR	Exon 10 of 10	NP_001309015.1
	AHCY	NM_001161766.2		c.*301T>G		3_prime_UTR	Exon 10 of 10	NP_001155238.1	P23526-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHCY	ENST00000217426.7	TSL:1 MANE Select	c.*301T>G		3_prime_UTR	Exon 10 of 10	ENSP00000217426.2	P23526-1
	AHCY	ENST00000538132.1	TSL:2	c.*301T>G		3_prime_UTR	Exon 10 of 10	ENSP00000442820.1	P23526-2
	AHCY	ENST00000480653.5	TSL:2	n.1748T>G		non_coding_transcript_exon	Exon 9 of 9

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;