rs34703687

Variant names:

• chr7-138105327-C-T
• rs34703687
• NM_005989.4:c.477C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_005989.4(AKR1D1):​c.477C>T​(p.Asp159Asp) 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:5
• Conservation: PhyloP100: -0.378
• Publications: 3 publications found

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]

AKR1D1 Gene-Disease associations (from GenCC):

• congenital bile acid synthesis defect 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000308006 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005989.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1D1	NM_005989.4	MANE Select	c.477C>T	p.Asp159Asp	synonymous	Exon 5 of 9	NP_005980.1	P51857-1
	AKR1D1	NM_001190907.2		c.477C>T	p.Asp159Asp	synonymous	Exon 5 of 8	NP_001177836.1	P51857-2
	AKR1D1	NM_001190906.2		c.457-1281C>T		intron	N/A	NP_001177835.1	P51857-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1D1	ENST00000242375.8	TSL:1 MANE Select	c.477C>T	p.Asp159Asp	synonymous	Exon 5 of 9	ENSP00000242375.3	P51857-1
	AKR1D1	ENST00000885436.1		c.606C>T	p.Asp202Asp	synonymous	Exon 7 of 11	ENSP00000555495.1
	AKR1D1	ENST00000885435.1		c.477C>T	p.Asp159Asp	synonymous	Exon 6 of 10	ENSP00000555494.1

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

GnomAD2 exomes AF: 0.00357 AC: 899 AN: 251478 AF XY: 0.00271

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 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

African (AFR) AF: 0.0501 AC: 1679 AN: 33480

American (AMR) AF: 0.00335 AC: 150 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111942

Other (OTH) AF: 0.00283 AC: 171 AN: 60394

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

African (AFR) AF: 0.0483 AC: 2005 AN: 41532

American (AMR) AF: 0.00497 AC: 76 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68028

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00639 Hom.: 13

Bravo AF: 0.0152

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Congenital bile acid synthesis defect 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		-0.38
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs34703687; hg19: chr7-137790073; COSMIC: COSV106091369;