rs17169518

chr7-138113680-G-A

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.856-10G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 1,611,990 control chromosomes in the GnomAD database, including 1,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (192 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1428 hom.)
• Consequence: AKR1D1 NM_005989.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001887
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.34

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=-0.98).
• BP6: Variant 7-138113680-G-A is Benign according to our data. Variant chr7-138113680-G-A is described in ClinVar as [Benign]. Clinvar id is 259894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1D1	NM_005989.4	c.856-10G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000242375.8
AKR1D1	NM_001190906.2	c.733-10G>A		splice_polypyrimidine_tract_variant, intron_variant
AKR1D1	NM_001190907.2	c.856-2940G>A		intron_variant
AKR1D1	XM_047420763.1	c.688-10G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1D1	ENST00000242375.8	c.856-10G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005989.4	P1
AKR1D1	ENST00000411726.6	c.733-10G>A		splice_polypyrimidine_tract_variant, intron_variant		2
AKR1D1	ENST00000432161.5	c.856-2940G>A		intron_variant		2
AKR1D1	ENST00000468877.2	n.879-10G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0454 AC: 6909 AN: 152082 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0436

Gnomad OTH AF: 0.0512

GnomAD3 exomes AF: 0.0339 AC: 8503 AN: 250802 Hom.: 194 AF XY: 0.0333 AC XY: 4516 AN XY: 135580

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.0207

Gnomad FIN exome AF: 0.0446

Gnomad NFE exome AF: 0.0404

Gnomad OTH exome AF: 0.0418

GnomAD4 exome AF: 0.0408 AC: 59600 AN: 1459790 Hom.: 1428 Cov.: 30 AF XY: 0.0401 AC XY: 29152 AN XY: 726338

Gnomad4 AFR exome AF: 0.0699

Gnomad4 AMR exome AF: 0.0220

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.0445

Gnomad4 NFE exome AF: 0.0440

Gnomad4 OTH exome AF: 0.0390

GnomAD4 genome AF: 0.0454 AC: 6912 AN: 152200 Hom.: 192 Cov.: 32 AF XY: 0.0443 AC XY: 3299 AN XY: 74418

Gnomad4 AFR AF: 0.0663

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.0207

Gnomad4 FIN AF: 0.0415

Gnomad4 NFE AF: 0.0437

Gnomad4 OTH AF: 0.0507

Alfa AF: 0.0439 Hom.: 129

Bravo AF: 0.0455

Asia WGS AF: 0.0170 AC: 58 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

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 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	-0.98
Cadd	Benign	0.0070
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.020		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: rs17169518; hg19: chr7-137798426;