rs34703687

Positions:

• chr7-138105327-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005989.4(AKR1D1):​c.477C>T​(p.Asp159=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,614,066 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (48 hom.)
• Consequence: AKR1D1 NM_005989.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.378

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 7-138105327-C-T is Benign according to our data. Variant chr7-138105327-C-T is described in ClinVar as [Benign]. Clinvar id is 259892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.378 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2112/152252) while in subpopulation AFR AF= 0.0483 (2005/41532). AF 95% confidence interval is 0.0465. There are 52 homozygotes in gnomad4. There are 974 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1D1	NM_005989.4	c.477C>T	p.Asp159=	synonymous_variant	5/9	ENST00000242375.8
AKR1D1	NM_001190907.2	c.477C>T	p.Asp159=	synonymous_variant	5/8
AKR1D1	XM_047420763.1	c.309C>T	p.Asp103=	synonymous_variant	4/8
AKR1D1	NM_001190906.2	c.457-1281C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1D1	ENST00000242375.8	c.477C>T	p.Asp159=	synonymous_variant	5/9	1	NM_005989.4	P1
AKR1D1	ENST00000432161.5	c.477C>T	p.Asp159=	synonymous_variant	5/8	2
AKR1D1	ENST00000411726.6	c.457-1281C>T		intron_variant		2
AKR1D1	ENST00000468877.2	n.387C>T		non_coding_transcript_exon_variant	5/10	2

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2108 AN: 152134 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00357 AC: 899 AN: 251478 Hom.: 22 AF XY: 0.00271 AC XY: 368 AN XY: 135908

Gnomad AFR exome AF: 0.0485

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00140 AC: 2049 AN: 1461814 Hom.: 48 Cov.: 31 AF XY: 0.00124 AC XY: 899 AN XY: 727210

Gnomad4 AFR exome AF: 0.0501

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.0139 AC: 2112 AN: 152252 Hom.: 52 Cov.: 32 AF XY: 0.0131 AC XY: 974 AN XY: 74428

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00604 Hom.: 10

Bravo AF: 0.0152

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Congenital bile acid synthesis defect 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	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

LitVar

Other links and lift over

dbSNP: rs34703687; hg19: chr7-137790073;