chr7-129225306-C-T

Variant names:

• chr7-129225306-C-T
• rs758474402
• NM_015328.4:c.230C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015328.4(AHCYL2):​c.230C>T​(p.Ala77Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,479,016 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: AHCYL2 NM_015328.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

Genes affected

AHCYL2 (HGNC:22204): (adenosylhomocysteinase like 2) The protein encoded by this gene acts as a homotetramer and may be involved in the conversion of S-adenosyl-L-homocysteine to L-homocysteine and adenosine. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017946988).
• BS2: High AC in GnomAd4 at 131 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHCYL2	NM_015328.4	c.230C>T	p.Ala77Val	missense_variant	Exon 1 of 17	ENST00000325006.8	NP_056143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHCYL2	ENST00000325006.8	c.230C>T	p.Ala77Val	missense_variant	Exon 1 of 17	1	NM_015328.4	ENSP00000315931.3
AHCYL2	ENST00000446544.6	c.230C>T	p.Ala77Val	missense_variant	Exon 1 of 17	1		ENSP00000413639.2

Frequencies

GnomAD3 genomes AF: 0.000862 AC: 131 AN: 151936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00623

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000795 AC: 64 AN: 80484 AF XY: 0.000670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00718

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.000478 AC: 635 AN: 1327080 Hom.: 4 Cov.: 34 AF XY: 0.000529 AC XY: 346 AN XY: 654230

African (AFR) AF: 0.0000373 AC: 1 AN: 26836

American (AMR) AF: 0.000188 AC: 5 AN: 26630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23430

East Asian (EAS) AF: 0.00 AC: 0 AN: 29014

South Asian (SAS) AF: 0.00 AC: 0 AN: 73218

European-Finnish (FIN) AF: 0.00514 AC: 170 AN: 33070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4298

European-Non Finnish (NFE) AF: 0.000410 AC: 433 AN: 1055462

Other (OTH) AF: 0.000472 AC: 26 AN: 55122

GnomAD4 genome AF: 0.000862 AC: 131 AN: 151936 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74202

African (AFR) AF: 0.0000724 AC: 3 AN: 41408

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00623 AC: 66 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000883 AC: 60 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000378

ExAC AF: 0.000197 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230C>T (p.A77V) alteration is located in exon 1 (coding exon 1) of the AHCYL2 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the alanine (A) at amino acid position 77 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.22
Sift	Benign	0.33	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.079	B;B
Vest4		0.29
MVP		0.35
MPC		1.4
ClinPred		0.14	T
GERP RS		3.8
PromoterAI		-0.073
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.31
Mutation Taster		=91/9	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

Publications

LitVar

Other links and lift over

dbSNP: rs758474402; hg19: chr7-128865147;