2-169091887-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001376924.1(DHRS9):​c.670C>T​(p.Leu224Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

DHRS9
NM_001376924.1 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.292
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.049737662).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DHRS9NM_001376924.1 linkc.670C>T p.Leu224Phe missense_variant 4/5 ENST00000674881.1 NP_001363853.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DHRS9ENST00000674881.1 linkc.670C>T p.Leu224Phe missense_variant 4/5 NM_001376924.1 ENSP00000502399.1 Q9BPW9-1
DHRS9ENST00000602501.5 linkc.670C>T p.Leu224Phe missense_variant 7/81 ENSP00000473337.1 Q9BPW9-1

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152074
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000598
AC:
15
AN:
250832
Hom.:
0
AF XY:
0.0000443
AC XY:
6
AN XY:
135574
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000654
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000349
AC:
51
AN:
1461728
Hom.:
0
Cov.:
30
AF XY:
0.0000316
AC XY:
23
AN XY:
727156
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000428
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152074
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74282
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000578
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000491
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 28, 2023The c.670C>T (p.L224F) alteration is located in exon 7 (coding exon 3) of the DHRS9 gene. This alteration results from a C to T substitution at nucleotide position 670, causing the leucine (L) at amino acid position 224 to be replaced by a phenylalanine (F). 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
0.15
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
12
DANN
Uncertain
0.98
DEOGEN2
Benign
0.21
T;T;.;T;.;T;T
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.095
N
LIST_S2
Benign
0.53
.;.;T;.;T;.;T
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.050
T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
1.4
L;L;.;L;.;L;L
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.84
.;N;N;N;N;N;N
REVEL
Benign
0.14
Sift
Benign
0.41
.;T;T;T;T;T;T
Sift4G
Benign
0.71
T;T;T;T;T;T;T
Polyphen
0.0020
B;B;.;B;.;B;B
Vest4
0.17
MVP
0.88
ClinPred
0.018
T
GERP RS
1.8
Varity_R
0.060
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137965309; hg19: chr2-169948397; API