2-169091792-G-A

Variant names:

• chr2-169091792-G-A
• rs200917304
• NM_001376924.1:c.575G>A

Variant summary

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

The NM_001376924.1(DHRS9):​c.575G>A​(p.Arg192Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,452,730 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DHRS9 NM_001376924.1 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.845

Genes affected

DHRS9 (HGNC:16888): (dehydrogenase/reductase 9) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. This protein demonstrates oxidoreductase activity toward hydroxysteroids and is able to convert 3-alpha-tetrahydroprogesterone to dihydroxyprogesterone and 3-alpha-androstanediol to dihydroxyprogesterone in the cytoplasm, and may additionally function as a transcriptional repressor in the nucleus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ENSG00000297257 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHRS9	NM_001376924.1	c.575G>A	p.Arg192Gln	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000674881.1	NP_001363853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHRS9	ENST00000674881.1	c.575G>A	p.Arg192Gln	missense_variant, splice_region_variant	Exon 4 of 5		NM_001376924.1	ENSP00000502399.1
DHRS9	ENST00000602501.5	c.575G>A	p.Arg192Gln	missense_variant, splice_region_variant	Exon 7 of 8	1		ENSP00000473337.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000806 AC: 2 AN: 248082 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.00000482 AC: 7 AN: 1452730 Hom.: 0 Cov.: 30 AF XY: 0.00000692 AC XY: 5 AN XY: 722144

African (AFR) AF: 0.00 AC: 0 AN: 33148

American (AMR) AF: 0.00 AC: 0 AN: 43814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39558

South Asian (SAS) AF: 0.0000469 AC: 4 AN: 85310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106276

Other (OTH) AF: 0.00 AC: 0 AN: 59952

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.575G>A (p.R192Q) alteration is located in exon 7 (coding exon 3) of the DHRS9 gene. This alteration results from a G to A substitution at nucleotide position 575, causing the arginine (R) at amino acid position 192 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;D;.;D;.;D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	.;.;D;.;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.63	N;N;.;N;.;N;N
PhyloP100		0.84
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.1	.;D;D;D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	.;D;D;D;D;D;D
Sift4G	Uncertain	0.032	D;D;T;D;T;D;D
Polyphen		1.0	D;D;.;D;.;D;D
Vest4		0.46
MutPred		0.48		Loss of stability (P = 0.148);Loss of stability (P = 0.148);.;Loss of stability (P = 0.148);.;Loss of stability (P = 0.148);Loss of stability (P = 0.148);
MVP		0.96
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.44
gMVP		0.78
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs200917304; hg19: chr2-169948302;