10-5204478-C-G

Position:

• chr10-5204478-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001818.5(AKR1C4):​c.354C>G​(p.Phe118Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKR1C4 NM_001818.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.211

Genes affected

AKR1C4 (HGNC:387): (aldo-keto reductase family 1 member C4) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34832868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C4	NM_001818.5	c.354C>G	p.Phe118Leu	missense_variant	3/9	ENST00000263126.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C4	ENST00000263126.3	c.354C>G	p.Phe118Leu	missense_variant	3/9	1	NM_001818.5	P1
AKR1C4	ENST00000380448.5	c.354C>G	p.Phe118Leu	missense_variant	5/11	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 118 of the AKR1C4 protein (p.Phe118Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with AKR1C4-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AKR1C4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.2
DANN	Benign	0.63
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.75	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.078
Sift	Benign	0.28	T;T
Sift4G	Benign	0.096	T;T
Polyphen		0.0010	B;B
Vest4		0.13
MutPred		0.69		Gain of disorder (P = 0.1052);Gain of disorder (P = 0.1052);
MVP		0.28
MPC		0.017
ClinPred		0.13	T
GERP RS		-6.0
Varity_R		0.54
gMVP		0.42

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: chr10-5246441;