7-138097885-C-T

Position:

• chr7-138097885-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000242375.8(AKR1D1):​c.398C>T​(p.Pro133Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. P133R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKR1D1 ENST00000242375.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.12

Genes affected

AKR1D1 (HGNC:388): (aldo-keto reductase family 1 member D1) The enzyme encoded by this gene is responsible for the catalysis of the 5-beta-reduction of bile acid intermediates and steroid hormones carrying a delta(4)-3-one structure. Deficiency of this enzyme may contribute to hepatic dysfunction. Three transcript variants encoding different isoforms have been found for this gene. Other variants may be present, but their full-length natures have not been determined yet. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1D1	NM_005989.4	c.398C>T	p.Pro133Leu	missense_variant	4/9	ENST00000242375.8	NP_005980.1
AKR1D1	NM_001190907.2	c.398C>T	p.Pro133Leu	missense_variant	4/8		NP_001177836.1
AKR1D1	NM_001190906.2	c.398C>T	p.Pro133Leu	missense_variant	4/8		NP_001177835.1
AKR1D1	XM_047420763.1	c.230C>T	p.Pro77Leu	missense_variant	3/8		XP_047276719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKR1D1	ENST00000242375.8	c.398C>T	p.Pro133Leu	missense_variant	4/9	1	NM_005989.4	ENSP00000242375	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-9.1	D;D;D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.82
MutPred		0.93		Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);.;
MVP		0.75
MPC		0.55
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.74

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: rs267606649; hg19: chr7-137782631;