rs1872929

Positions:

• chr7-138116667-A-C
• chr7-138116667-A-G
• chr7-138116667-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005989.4(AKR1D1):​c.*5A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,613,284 control chromosomes in the GnomAD database, including 505,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49563 hom., cov: 32)
  • Exomes 𝑓: 0.79 (455771 hom.)
• Consequence: AKR1D1 NM_005989.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.358

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-138116667-A-C is Benign according to our data. Variant chr7-138116667-A-C is described in ClinVar as [Benign]. Clinvar id is 259891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-138116667-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1D1	NM_005989.4	c.*5A>C		3_prime_UTR_variant	9/9	ENST00000242375.8	NP_005980.1
AKR1D1	NM_001190906.2	c.*5A>C		3_prime_UTR_variant	8/8		NP_001177835.1
AKR1D1	NM_001190907.2	c.*30A>C		3_prime_UTR_variant	8/8		NP_001177836.1
AKR1D1	XM_047420763.1	c.*5A>C		3_prime_UTR_variant	8/8		XP_047276719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKR1D1	ENST00000242375.8	c.*5A>C		3_prime_UTR_variant	9/9	1	NM_005989.4	ENSP00000242375	P1
AKR1D1	ENST00000411726.6	c.*5A>C		3_prime_UTR_variant	8/8	2		ENSP00000402374
AKR1D1	ENST00000432161.5	c.*30A>C		3_prime_UTR_variant	8/8	2		ENSP00000389197
AKR1D1	ENST00000468877.2	n.1009A>C		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.805 AC: 122307 AN: 152014 Hom.: 49516 Cov.: 32

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.858

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.735

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.796

Gnomad OTH AF: 0.787

GnomAD3 exomes AF: 0.772 AC: 194140 AN: 251414 Hom.: 75585 AF XY: 0.775 AC XY: 105295 AN XY: 135886

Gnomad AFR exome AF: 0.876

Gnomad AMR exome AF: 0.638

Gnomad ASJ exome AF: 0.784

Gnomad EAS exome AF: 0.738

Gnomad SAS exome AF: 0.768

Gnomad FIN exome AF: 0.818

Gnomad NFE exome AF: 0.795

Gnomad OTH exome AF: 0.779

GnomAD4 exome AF: 0.789 AC: 1152565 AN: 1461152 Hom.: 455771 Cov.: 43 AF XY: 0.789 AC XY: 573367 AN XY: 726914

Gnomad4 AFR exome AF: 0.879

Gnomad4 AMR exome AF: 0.641

Gnomad4 ASJ exome AF: 0.780

Gnomad4 EAS exome AF: 0.741

Gnomad4 SAS exome AF: 0.771

Gnomad4 FIN exome AF: 0.815

Gnomad4 NFE exome AF: 0.794

Gnomad4 OTH exome AF: 0.788

GnomAD4 genome AF: 0.805 AC: 122410 AN: 152132 Hom.: 49563 Cov.: 32 AF XY: 0.802 AC XY: 59668 AN XY: 74386

Gnomad4 AFR AF: 0.877

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.779

Gnomad4 EAS AF: 0.735

Gnomad4 SAS AF: 0.772

Gnomad4 FIN AF: 0.814

Gnomad4 NFE AF: 0.796

Gnomad4 OTH AF: 0.788

Alfa AF: 0.788 Hom.: 102100

Bravo AF: 0.795

Asia WGS AF: 0.772 AC: 2682 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital bile acid synthesis defect 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.59

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: rs1872929; hg19: chr7-137801413;