10-4967001-T-C

Variant names:

• chr10-4967001-T-C
• rs11548049
• NM_001353.6:c.327T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP7 BS2

The NM_001353.6(AKR1C1):​c.327T>C​(p.Asp109Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00749 in 1,613,436 control chromosomes in the GnomAD database, including 45 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 0.0072 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (41 hom.)
• Consequence: AKR1C1 NM_001353.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 5 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.052).
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353.6. 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
	AKR1C1	NM_001353.6	MANE Select	c.327T>C	p.Asp109Asp	synonymous	Exon 3 of 9	NP_001344.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C1	ENST00000380872.9	TSL:1 MANE Select	c.327T>C	p.Asp109Asp	synonymous	Exon 3 of 9	ENSP00000370254.4	Q04828
	AKR1C1	ENST00000970520.1		c.327T>C	p.Asp109Asp	synonymous	Exon 3 of 9	ENSP00000640579.1
	AKR1C1	ENST00000859341.1		c.327T>C	p.Asp109Asp	synonymous	Exon 3 of 8	ENSP00000529400.1

Frequencies

GnomAD3 genomes AF: 0.00714 AC: 1086 AN: 152202 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00872

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00601 AC: 1509 AN: 251054 AF XY: 0.00601

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.00573

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00895

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.00752 AC: 10986 AN: 1461116 Hom.: 41 Cov.: 30 AF XY: 0.00736 AC XY: 5349 AN XY: 726856

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

African (AFR) AF: 0.00741 AC: 248 AN: 33458

American (AMR) AF: 0.00602 AC: 269 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00666 AC: 174 AN: 26118

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86234

European-Finnish (FIN) AF: 0.00326 AC: 174 AN: 53414

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5762

European-Non Finnish (NFE) AF: 0.00854 AC: 9496 AN: 1111380

Other (OTH) AF: 0.00870 AC: 525 AN: 60356

⚠️ 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: 0.00716 AC: 1091 AN: 152320 Hom.: 4 Cov.: 33 AF XY: 0.00698 AC XY: 520 AN XY: 74502

African (AFR) AF: 0.00777 AC: 323 AN: 41560

American (AMR) AF: 0.00633 AC: 97 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00872 AC: 593 AN: 68022

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.125 Hom.: 3006

Bravo AF: 0.00755

EpiCase AF: 0.00943

EpiControl AF: 0.00996

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.6
DANN	Benign	0.34
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs11548049; hg19: chr10-5009193; COSMIC: COSV66499051; COSMIC: COSV66499051;