chr1-45568680-C-T

Variant names:

• chr1-45568680-C-T
• NM_153326.3:c.748C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153326.3(AKR1A1):​c.748C>T​(p.Leu250Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AKR1A1 NM_153326.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

AKR1A1 (HGNC:380): (aldo-keto reductase family 1 member A1) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. This member, also known as aldehyde reductase, is involved in the reduction of biogenic and xenobiotic aldehydes and is present in virtually every tissue. Multiple alternatively spliced transcript variants of this gene exist, all encoding the same protein. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1A1	NM_153326.3	c.748C>T	p.Leu250Phe	missense_variant	Exon 6 of 9	ENST00000351829.9	NP_697021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1A1	ENST00000351829.9	c.748C>T	p.Leu250Phe	missense_variant	Exon 6 of 9	1	NM_153326.3	ENSP00000312606.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461128 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726872

Gnomad4 AFR exome AF: 0.00

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.748C>T (p.L250F) alteration is located in exon 7 (coding exon 5) of the AKR1A1 gene. This alteration results from a C to T substitution at nucleotide position 748, causing the leucine (L) at amino acid position 250 to be replaced by a phenylalanine (F). 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	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	.;D;.
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.3	M;M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.68
MutPred		0.67		Loss of catalytic residue at L250 (P = 0.0064);Loss of catalytic residue at L250 (P = 0.0064);Loss of catalytic residue at L250 (P = 0.0064);
MVP		0.54
MPC		0.39
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.89
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-46034352;