chr20-34285641-G-A

Variant names:

• chr20-34285641-G-A
• rs17091705
• NM_000687.4:c.973-7C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000687.4(AHCY):​c.973-7C>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 0.0198 in 1,612,020 control chromosomes in the GnomAD database, including 5,500 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2864 hom., cov: 32)
  • Exomes 𝑓: 0.011 (2636 hom.)
• Consequence: AHCY NM_000687.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002591
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.36
• Publications: 5 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

ENSG00000272945 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 20-34285641-G-A is Benign according to our data. Variant chr20-34285641-G-A is described in ClinVar as Benign. ClinVar VariationId is 338270.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHCY	NM_000687.4	MANE Select	c.973-7C>T		splice_region intron	N/A	NP_000678.1
	AHCY	NM_001322086.2		c.979-7C>T		splice_region intron	N/A	NP_001309015.1
	AHCY	NM_001362750.2		c.973-7C>T		splice_region intron	N/A	NP_001349679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHCY	ENST00000217426.7	TSL:1 MANE Select	c.973-7C>T		splice_region intron	N/A	ENSP00000217426.2
	AHCY	ENST00000538132.1	TSL:2	c.889-7C>T		splice_region intron	N/A	ENSP00000442820.1
	AHCY	ENST00000480653.5	TSL:2	n.1121-7C>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16073 AN: 151944 Hom.: 2863 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0476

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000971

Gnomad OTH AF: 0.0723

GnomAD2 exomes AF: 0.0273 AC: 6767 AN: 248266 AF XY: 0.0204

Gnomad AFR exome AF: 0.371

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000568

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0108 AC: 15777 AN: 1459958 Hom.: 2636 Cov.: 31 AF XY: 0.00931 AC XY: 6766 AN XY: 726374

African (AFR) AF: 0.379 AC: 12684 AN: 33470

American (AMR) AF: 0.0208 AC: 928 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 55 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.000928 AC: 80 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51758

Middle Eastern (MID) AF: 0.0156 AC: 90 AN: 5768

European-Non Finnish (NFE) AF: 0.000402 AC: 447 AN: 1111870

Other (OTH) AF: 0.0247 AC: 1489 AN: 60360

GnomAD4 genome AF: 0.106 AC: 16087 AN: 152062 Hom.: 2864 Cov.: 32 AF XY: 0.102 AC XY: 7594 AN XY: 74360

African (AFR) AF: 0.365 AC: 15121 AN: 41408

American (AMR) AF: 0.0475 AC: 725 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000971 AC: 66 AN: 67994

Other (OTH) AF: 0.0716 AC: 151 AN: 2110

Alfa AF: 0.0408 Hom.: 2906

Bravo AF: 0.121

Asia WGS AF: 0.0160 AC: 58 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.74
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0020
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: rs17091705; hg19: chr20-32873447;