NM_001818.5:c.105A>G

Variant names:

• chr10-5200201-A-G
• rs17306779
• NM_001818.5:c.105A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001818.5(AKR1C4):​c.105A>G​(p.Val35Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,736 control chromosomes in the GnomAD database, including 39,315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2875 hom., cov: 32)
  • Exomes 𝑓: 0.22 (36440 hom.)
• Consequence: AKR1C4 NM_001818.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.62
• Publications: 16 publications found

Genes affected

AKR1C4 (HGNC:387): (aldo-keto reductase family 1 member C4) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. [provided by RefSeq, Jul 2008]

AKR1C4 Gene-Disease associations (from GenCC):

• 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-5200201-A-G is Benign according to our data. Variant chr10-5200201-A-G is described in ClinVar as Benign. ClinVar VariationId is 1229360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C4	NM_001818.5	c.105A>G	p.Val35Val	synonymous_variant	Exon 2 of 9	ENST00000263126.3	NP_001809.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C4	ENST00000263126.3	c.105A>G	p.Val35Val	synonymous_variant	Exon 2 of 9	1	NM_001818.5	ENSP00000263126.1
AKR1C4	ENST00000380448.5	c.105A>G	p.Val35Val	synonymous_variant	Exon 4 of 11	5		ENSP00000369814.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28388 AN: 152188 Hom.: 2874 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.205 AC: 51326 AN: 250916 AF XY: 0.205

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.220 AC: 320870 AN: 1461430 Hom.: 36440 Cov.: 32 AF XY: 0.217 AC XY: 157978 AN XY: 726990

African (AFR) AF: 0.111 AC: 3701 AN: 33472

American (AMR) AF: 0.244 AC: 10918 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4867 AN: 26106

East Asian (EAS) AF: 0.101 AC: 4027 AN: 39686

South Asian (SAS) AF: 0.164 AC: 14096 AN: 86176

European-Finnish (FIN) AF: 0.199 AC: 10635 AN: 53394

Middle Eastern (MID) AF: 0.173 AC: 995 AN: 5766

European-Non Finnish (NFE) AF: 0.233 AC: 259036 AN: 1111748

Other (OTH) AF: 0.209 AC: 12595 AN: 60382

GnomAD4 genome AF: 0.186 AC: 28402 AN: 152306 Hom.: 2875 Cov.: 32 AF XY: 0.185 AC XY: 13791 AN XY: 74472

African (AFR) AF: 0.113 AC: 4689 AN: 41576

American (AMR) AF: 0.227 AC: 3472 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3472

East Asian (EAS) AF: 0.136 AC: 705 AN: 5176

South Asian (SAS) AF: 0.163 AC: 786 AN: 4828

European-Finnish (FIN) AF: 0.190 AC: 2012 AN: 10616

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15467 AN: 68010

Other (OTH) AF: 0.184 AC: 390 AN: 2114

Alfa AF: 0.215 Hom.: 2765

Bravo AF: 0.187

Asia WGS AF: 0.144 AC: 503 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.31
DANN	Benign	0.55
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs17306779; hg19: chr10-5242164; COSMIC: COSV54122750; COSMIC: COSV54122750;