10-4968380-A-G

Variant names:

• chr10-4968380-A-G
• rs1138600
• NM_001353.6:c.441A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001353.6(AKR1C1):​c.441A>G​(p.Thr147Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 148,896 control chromosomes in the GnomAD database, including 73,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (73694 hom., cov: 24)
  • Exomes 𝑓: 1.0 (693643 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKR1C1 NM_001353.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -10.2
• Publications: 13 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.017).
• BP6: Variant 10-4968380-A-G is Benign according to our data. Variant chr10-4968380-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 768347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-10.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C1	NM_001353.6	MANE Select	c.441A>G	p.Thr147Thr	synonymous	Exon 4 of 9	NP_001344.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C1	ENST00000380872.9	TSL:1 MANE Select	c.441A>G	p.Thr147Thr	synonymous	Exon 4 of 9	ENSP00000370254.4
	AKR1C1	ENST00000442997.5	TSL:3	c.339A>G	p.Thr113Thr	synonymous	Exon 4 of 7	ENSP00000416415.1
	AKR1C1	ENST00000380859.1	TSL:3	c.447A>G	p.Thr149Thr	synonymous	Exon 4 of 6	ENSP00000370240.1

Frequencies

GnomAD3 genomes AF: 0.995 AC: 148022 AN: 148782 Hom.: 73634 Cov.: 24

Gnomad AFR AF: 0.991

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 0.989

Gnomad EAS AF: 0.992

Gnomad SAS AF: 0.996

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.997 AC: 179348 AN: 179892 AF XY: 0.997

Gnomad AFR exome AF: 0.990

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 0.997

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.997

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.997 AC: 1391089 AN: 1394908 Hom.: 693643 Cov.: 27 AF XY: 0.997 AC XY: 690404 AN XY: 692326

African (AFR) AF: 0.990 AC: 32138 AN: 32450

American (AMR) AF: 0.999 AC: 41664 AN: 41722

Ashkenazi Jewish (ASJ) AF: 0.992 AC: 23611 AN: 23812

East Asian (EAS) AF: 0.996 AC: 38392 AN: 38528

South Asian (SAS) AF: 0.996 AC: 81303 AN: 81670

European-Finnish (FIN) AF: 0.998 AC: 51665 AN: 51768

Middle Eastern (MID) AF: 0.998 AC: 5494 AN: 5506

European-Non Finnish (NFE) AF: 0.998 AC: 1059094 AN: 1061528

Other (OTH) AF: 0.997 AC: 57728 AN: 57924

GnomAD4 genome AF: 0.995 AC: 148139 AN: 148896 Hom.: 73694 Cov.: 24 AF XY: 0.995 AC XY: 72332 AN XY: 72716

African (AFR) AF: 0.991 AC: 40333 AN: 40704

American (AMR) AF: 0.995 AC: 14890 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 3326 AN: 3362

East Asian (EAS) AF: 0.992 AC: 4871 AN: 4910

South Asian (SAS) AF: 0.997 AC: 4571 AN: 4586

European-Finnish (FIN) AF: 0.998 AC: 10408 AN: 10424

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 66535 AN: 66728

Other (OTH) AF: 0.994 AC: 2010 AN: 2022

Alfa AF: 0.994 Hom.: 12477

Bravo AF: 0.996

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.8
DANN	Benign	0.18
PhyloP100		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1138600; hg19: chr10-5010572; COSMIC: COSV66498428; COSMIC: COSV66498428;