chr7-138088664-G-A

Position:

• chr7-138088664-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_005989.4(AKR1D1):​c.157G>A​(p.Asp53Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,826 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: 0.0000048 (0 hom.)
• Consequence: AKR1D1 NM_005989.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.05

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 8 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity AK1D1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1D1	NM_005989.4	c.157G>A	p.Asp53Asn	missense_variant	2/9	ENST00000242375.8
AKR1D1	NM_001190907.2	c.157G>A	p.Asp53Asn	missense_variant	2/8
AKR1D1	NM_001190906.2	c.157G>A	p.Asp53Asn	missense_variant	2/8
AKR1D1	XM_047420763.1	c.94-3104G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1D1	ENST00000242375.8	c.157G>A	p.Asp53Asn	missense_variant	2/9	1	NM_005989.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251124 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135694

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 SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461826 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727210

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: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital bile acid synthesis defect 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Jun 21, 2023

This homozygous variant c.157G>A (p.Asp53Asn) has been identified in a proband who presented with jaundice, high hepatic transaminases and failure to thrive. This variant is found in gnomAD-0.0012% and ExAc-0.0008%. This variant is also present in an 8 year old unaffected female sibling in the homozygous state. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with AKR1D1-related conditions. This variant is present in population databases (rs766798731, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 53 of the AKR1D1 protein (p.Asp53Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.1	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.94
MutPred		0.92		Loss of catalytic residue at D53 (P = 0.0123);Loss of catalytic residue at D53 (P = 0.0123);Loss of catalytic residue at D53 (P = 0.0123);
MVP		0.87
MPC		0.54
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.97

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: rs766798731; hg19: chr7-137773410;