1-19311976-C-A

Variant names:

• chr1-19311976-C-A
• rs2093777729
• NM_003689.4:c.149G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003689.4(AKR7A2):​c.149G>T​(p.Arg50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000852 in 1,408,338 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: AKR7A2 NM_003689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR7A2	NM_003689.4	c.149G>T	p.Arg50Leu	missense_variant	Exon 1 of 7	ENST00000235835.8	NP_003680.2
AKR7A2	NM_001320979.1	c.149G>T	p.Arg50Leu	missense_variant	Exon 1 of 6		NP_001307908.1
AKR7A2	XM_047433095.1	c.149G>T	p.Arg50Leu	missense_variant	Exon 1 of 4		XP_047289051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR7A2	ENST00000235835.8	c.149G>T	p.Arg50Leu	missense_variant	Exon 1 of 7	1	NM_003689.4	ENSP00000235835.3
AKR7A2	ENST00000330072.9	c.119G>T	p.Arg40Leu	missense_variant	Exon 1 of 6	2		ENSP00000339084.5
AKR7A2	ENST00000492217.1	n.128G>T		non_coding_transcript_exon_variant	Exon 1 of 3	2
AKR7A2	ENST00000489286.5	c.-71G>T		upstream_gene_variant		5		ENSP00000419936.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000852 AC: 12 AN: 1408338 Hom.: 0 Cov.: 38 AF XY: 0.00000862 AC XY: 6 AN XY: 696300

Gnomad4 AFR exome AF: 0.0000313

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149G>T (p.R50L) alteration is located in exon 1 (coding exon 1) of the AKR7A2 gene. This alteration results from a G to T substitution at nucleotide position 149, causing the arginine (R) at amino acid position 50 to be replaced by a leucine (L). 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.13
Sift	Benign	0.11	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.066	B;.
Vest4		0.45
MutPred		0.38		Loss of MoRF binding (P = 0.0207);.;
MVP		0.52
MPC		1.9
ClinPred		0.91	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.78
gMVP		0.27

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: rs2093777729; hg19: chr1-19638470;