rs754080850

Variant names:

• chr7-134450812-G-A
• rs754080850
• NM_001628.4:c.325C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-134450812-G-A
• chr7-134450812-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001628.4(AKR1B1):​c.325C>T​(p.Leu109Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L109V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: AKR1B1 NM_001628.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.83
• Publications: 0 publications found

Genes affected

AKR1B1 (HGNC:381): (aldo-keto reductase family 1 member B) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. This member catalyzes the reduction of a number of aldehydes, including the aldehyde form of glucose, and is thereby implicated in the development of diabetic complications by catalyzing the reduction of glucose to sorbitol. Multiple pseudogenes have been identified for this gene. The nomenclature system used by the HUGO Gene Nomenclature Committee to define human aldo-keto reductase family members is known to differ from that used by the Mouse Genome Informatics database. [provided by RefSeq, Feb 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001628.4. 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
	AKR1B1	NM_001628.4	MANE Select	c.325C>T	p.Leu109Phe	missense	Exon 3 of 10	NP_001619.1	P15121
	AKR1B1	NM_001346142.1		c.-108C>T		5_prime_UTR	Exon 3 of 10	NP_001333071.1
	AKR1B1	NR_144376.2		n.363C>T		non_coding_transcript_exon	Exon 3 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1B1	ENST00000285930.9	TSL:1 MANE Select	c.325C>T	p.Leu109Phe	missense	Exon 3 of 10	ENSP00000285930.3	P15121
	AKR1B1	ENST00000465351.5	TSL:1	n.365C>T		non_coding_transcript_exon	Exon 3 of 9
	AKR1B1	ENST00000467829.1	TSL:1	n.422C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251430 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.70		Gain of catalytic residue at L109 (P = 0.1168)
MVP		0.63
MPC		0.84
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.94
gMVP		0.87
Mutation Taster		=20/80	disease causing

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: rs754080850; hg19: chr7-134135564;