10-4967567-G-T

Variant names:

• chr10-4967567-G-T
• rs2904804
• NM_001353.6:c.369+524G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001353.6(AKR1C1):​c.369+524G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 150,154 control chromosomes in the GnomAD database, including 32,181 homozygotes. 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: 𝑓 0.65 (32181 hom., cov: 28)
  • Exomes 𝑓: 0.55 (104454 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKR1C1 NM_001353.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385
• Publications: 10 publications found

Genes affected

AKR1C1 (HGNC:384): (aldo-keto reductase family 1 member C1) 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 reaction of progesterone to the inactive form 20-alpha-hydroxy-progesterone. 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C1	NM_001353.6	c.369+524G>T		intron_variant	Intron 3 of 8	ENST00000380872.9	NP_001344.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C1	ENST00000380872.9	c.369+524G>T		intron_variant	Intron 3 of 8	1	NM_001353.6	ENSP00000370254.4
AKR1C1	ENST00000477661.1	n.1085G>T		non_coding_transcript_exon_variant	Exon 3 of 8	5
AKR1C1	ENST00000442997.5	c.267+524G>T		intron_variant	Intron 3 of 6	3		ENSP00000416415.1
AKR1C1	ENST00000380859.1	c.375+524G>T		intron_variant	Intron 3 of 5	3		ENSP00000370240.1

Frequencies

GnomAD3 genomes AF: 0.653 AC: 98007 AN: 150042 Hom.: 32141 Cov.: 28

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.689

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.663

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.551 AC: 349891 AN: 635412 Hom.: 104454 Cov.: 9 AF XY: 0.551 AC XY: 162411 AN XY: 294534

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

African (AFR) AF: 0.658 AC: 7422 AN: 11276

American (AMR) AF: 0.674 AC: 531 AN: 788

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 2414 AN: 3876

East Asian (EAS) AF: 0.772 AC: 2113 AN: 2738

South Asian (SAS) AF: 0.526 AC: 6519 AN: 12398

European-Finnish (FIN) AF: 0.727 AC: 128 AN: 176

Middle Eastern (MID) AF: 0.555 AC: 680 AN: 1226

European-Non Finnish (NFE) AF: 0.547 AC: 318484 AN: 582232

Other (OTH) AF: 0.560 AC: 11600 AN: 20702

⚠️ 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 AF: 0.653 AC: 98095 AN: 150154 Hom.: 32181 Cov.: 28 AF XY: 0.659 AC XY: 48308 AN XY: 73330

African (AFR) AF: 0.683 AC: 27845 AN: 40744

American (AMR) AF: 0.689 AC: 10382 AN: 15070

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2235 AN: 3456

East Asian (EAS) AF: 0.811 AC: 4119 AN: 5076

South Asian (SAS) AF: 0.565 AC: 2666 AN: 4722

European-Finnish (FIN) AF: 0.761 AC: 7965 AN: 10464

Middle Eastern (MID) AF: 0.589 AC: 172 AN: 292

European-Non Finnish (NFE) AF: 0.605 AC: 40782 AN: 67366

Other (OTH) AF: 0.667 AC: 1379 AN: 2066

Alfa AF: 0.621 Hom.: 27000

Bravo AF: 0.654

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.37
PhyloP100		-0.39
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: rs2904804; hg19: chr10-5009759;