1-19308225-C-T

Variant names:

• chr1-19308225-C-T
• rs765791064
• NM_003689.4:c.524G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003689.4(AKR7A2):​c.524G>A​(p.Ser175Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S175T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AKR7A2 NM_003689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.40
• Publications: 1 publications found

Genes affected

AKR7A2 (HGNC:389): (aldo-keto reductase family 7 member A2) The protein encoded by this gene belongs to the aldo/keto reductase (AKR) superfamily and AKR7 family, which are involved in the detoxification of aldehydes and ketones. The AKR7 family consists of 3 genes that are present in a cluster on the p arm of chromosome 1. This protein, thought to be localized in the golgi, catalyzes the NADPH-dependent reduction of succinic semialdehyde to the endogenous neuromodulator, gamma-hydroxybutyrate. It may also function as a detoxication enzyme in the reduction of aflatoxin B1 and 2-carboxybenzaldehyde. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40303558).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003689.4. 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
	AKR7A2	NM_003689.4	MANE Select	c.524G>A	p.Ser175Asn	missense	Exon 3 of 7	NP_003680.2
	AKR7A2	NM_001320979.1		c.486+230G>A		intron	N/A	NP_001307908.1	B4DZX4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR7A2	ENST00000235835.8	TSL:1 MANE Select	c.524G>A	p.Ser175Asn	missense	Exon 3 of 7	ENSP00000235835.3	O43488
	AKR7A2	ENST00000489286.5	TSL:5	c.305G>A	p.Ser102Asn	missense	Exon 3 of 5	ENSP00000419936.1	H7C5H7
	AKR7A2	ENST00000330072.10	TSL:2	c.486+230G>A		intron	N/A	ENSP00000339084.5	H3BLU7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.030	T
Eigen	Benign	0.094
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.4
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.67	P
Vest4		0.42
MutPred		0.66		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.43
MPC		0.16
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.91
gMVP		0.24
Mutation Taster		=65/35	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: rs765791064; hg19: chr1-19634719;