chr2-169083416-T-C

Position:

• chr2-169083416-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001376924.1(DHRS9):​c.401T>C​(p.Ile134Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DHRS9 NM_001376924.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.11

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHRS9	NM_001376924.1	c.401T>C	p.Ile134Thr	missense_variant	3/5	ENST00000674881.1	NP_001363853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHRS9	ENST00000674881.1	c.401T>C	p.Ile134Thr	missense_variant	3/5		NM_001376924.1	ENSP00000502399.1
DHRS9	ENST00000602501.5	c.401T>C	p.Ile134Thr	missense_variant	6/8	1		ENSP00000473337.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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 30, 2023

The c.401T>C (p.I134T) alteration is located in exon 6 (coding exon 2) of the DHRS9 gene. This alteration results from a T to C substitution at nucleotide position 401, causing the isoleucine (I) at amino acid position 134 to be replaced by a threonine (T). 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	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D;.;D;D;D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	.;.;D;.;.;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.7	L;L;.;L;L;L
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.5	.;D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	.;D;D;D;D;D
Sift4G	Uncertain	0.045	D;D;T;D;D;D
Polyphen		0.15	B;B;.;B;B;B
Vest4		0.47
MutPred		0.84		Gain of disorder (P = 0.0426);Gain of disorder (P = 0.0426);.;Gain of disorder (P = 0.0426);Gain of disorder (P = 0.0426);Gain of disorder (P = 0.0426);
MVP		0.97
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.59
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs768120176; hg19: chr2-169939926;