2-169091888-T-A

Position:

• chr2-169091888-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001376924.1(DHRS9):​c.671T>A​(p.Leu224His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DHRS9 NM_001376924.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.790

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07388857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHRS9	NM_001376924.1	c.671T>A	p.Leu224His	missense_variant	4/5	ENST00000674881.1	NP_001363853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHRS9	ENST00000674881.1	c.671T>A	p.Leu224His	missense_variant	4/5		NM_001376924.1	ENSP00000502399.1
DHRS9	ENST00000602501.5	c.671T>A	p.Leu224His	missense_variant	7/8	1		ENSP00000473337.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461756 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Sep 27, 2021

The c.671T>A (p.L224H) alteration is located in exon 7 (coding exon 3) of the DHRS9 gene. This alteration results from a T to A substitution at nucleotide position 671, causing the leucine (L) at amino acid position 224 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.15	T;T;.;T;.;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.46	.;.;T;.;T;.;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.074	T;T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.3	L;L;.;L;.;L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.090	.;N;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.39	.;T;T;T;T;T;T
Sift4G	Benign	0.56	T;T;T;T;T;T;T
Polyphen		0.0030	B;B;.;B;.;B;B
Vest4		0.21
MutPred		0.43		Loss of ubiquitination at K222 (P = 0.0982);Loss of ubiquitination at K222 (P = 0.0982);.;Loss of ubiquitination at K222 (P = 0.0982);.;Loss of ubiquitination at K222 (P = 0.0982);Loss of ubiquitination at K222 (P = 0.0982);
MVP		0.72
ClinPred		0.044	T
GERP RS		3.5
Varity_R		0.12
gMVP		0.65

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: rs1373035714; hg19: chr2-169948398;