10-5204621-C-T

Variant names:

• chr10-5204621-C-T
• rs11253042
• NM_001818.5:c.369+128C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001818.5(AKR1C4):​c.369+128C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 654,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: AKR1C4 NM_001818.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• Publications: 12 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001818.5. 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
	AKR1C4	NM_001818.5	MANE Select	c.369+128C>T		intron	N/A	NP_001809.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C4	ENST00000263126.3	TSL:1 MANE Select	c.369+128C>T		intron	N/A	ENSP00000263126.1	P17516
	AKR1C4	ENST00000901611.1		c.369+128C>T		intron	N/A	ENSP00000571670.1
	AKR1C4	ENST00000380448.5	TSL:5	c.369+128C>T		intron	N/A	ENSP00000369814.1	P17516

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241508 AF XY: 0.00000762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000153 AC: 1 AN: 654276 Hom.: 0 Cov.: 8 AF XY: 0.00000282 AC XY: 1 AN XY: 355130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18196

American (AMR) AF: 0.00 AC: 0 AN: 43454

Ashkenazi Jewish (ASJ) AF: 0.0000473 AC: 1 AN: 21136

East Asian (EAS) AF: 0.00 AC: 0 AN: 35996

South Asian (SAS) AF: 0.00 AC: 0 AN: 69510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 382412

Other (OTH) AF: 0.00 AC: 0 AN: 34112

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000450 Hom.: 24075

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.18
DANN	Benign	0.60
PhyloP100		-1.7

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: rs11253042; hg19: chr10-5246584;