2-169081830-T-G

Position:

• chr2-169081830-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001376924.1(DHRS9):​c.249T>G​(p.Asp83Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHRS9 NM_001376924.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.484

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHRS9	NM_001376924.1	c.249T>G	p.Asp83Glu	missense_variant	2/5	ENST00000674881.1	NP_001363853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHRS9	ENST00000674881.1	c.249T>G	p.Asp83Glu	missense_variant	2/5		NM_001376924.1	ENSP00000502399.1
DHRS9	ENST00000602501.5	c.249T>G	p.Asp83Glu	missense_variant	5/8	1		ENSP00000473337.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2024

The c.249T>G (p.D83E) alteration is located in exon 5 (coding exon 1) of the DHRS9 gene. This alteration results from a T to G substitution at nucleotide position 249, causing the aspartic acid (D) at amino acid position 83 to be replaced by a glutamic acid (E). 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	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;D;D;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;.;T;.;.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;M;M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.5	.;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0080	.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D
Vest4		0.68
MutPred		0.95		Gain of catalytic residue at D83 (P = 0.0803);Gain of catalytic residue at D83 (P = 0.0803);.;Gain of catalytic residue at D83 (P = 0.0803);Gain of catalytic residue at D83 (P = 0.0803);Gain of catalytic residue at D83 (P = 0.0803);
MVP		0.99
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.55
gMVP		0.78

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-169938340;