chr10-5157733-C-T

Variant names:

• chr10-5157733-C-T
• rs1781935
• NM_001395972.1:c.757G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001395972.1(AKR1C8):​c.757G>A​(p.Gly253Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 320,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict 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: 0.0000031 (0 hom.)
• Consequence: AKR1C8 NM_001395972.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0120
• Publications: 0 publications found

Genes affected

AKR1C8 (HGNC:23469): (aldo-keto reductase family 1 member C8) Predicted to enable D-threo-aldose 1-dehydrogenase activity; aldo-keto reductase (NADP) activity; and estradiol 17-beta-dehydrogenase activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12620342).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395972.1. 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
	AKR1C8	NM_001395972.1	MANE Select	c.757G>A	p.Gly253Arg	missense	Exon 7 of 9	NP_001382901.1
	AKR1C8	NR_027916.3		n.749G>A		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C8	ENST00000648824.2	MANE Select	c.757G>A	p.Gly253Arg	missense	Exon 7 of 9	ENSP00000496804.1
	AKR1C8	ENST00000578467.2	TSL:2	n.786G>A		non_coding_transcript_exon	Exon 7 of 8
	AKR1C8	ENST00000584929.7	TSL:6	n.*423G>A		non_coding_transcript_exon	Exon 8 of 10	ENSP00000496857.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000312 AC: 1 AN: 320098 Hom.: 0 Cov.: 0 AF XY: 0.00000553 AC XY: 1 AN XY: 180756

⚠️ 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: 8630

American (AMR) AF: 0.00 AC: 0 AN: 27262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10788

East Asian (EAS) AF: 0.00 AC: 0 AN: 9212

South Asian (SAS) AF: 0.0000166 AC: 1 AN: 60306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2784

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 158986

Other (OTH) AF: 0.00 AC: 0 AN: 14332

⚠️ 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.018
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.13	T
PhyloP100		-0.012
gMVP		0.36

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1781935; hg19: chr10-5199934;