Genetic Variant DHRS7:p.Leu217Phe (chr14-60150172-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_016029.4(DHRS7):c.649C>T(p.Leu217Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000402 in 1,491,818 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: 𝑓 0.000021 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

DHRS7
NM_016029.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.30

Variant links:

Genes affected

DHRS7 (HGNC:21524): (dehydrogenase/reductase 7) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) family, which has over 46,000 members. Members in this family are enzymes that metabolize many different compounds, such as steroid hormones, prostaglandins, retinoids, lipids and xenobiotics. [provided by RefSeq, Apr 2016]

DHRS7 links:

PCNX4 (HGNC:20349): (pecanex 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

PCNX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHRS7	NM_016029.4 link	c.649C>T	p.Leu217Phe	missense_variant	Exon 5 of 7	ENST00000557185.6	NP_057113.1	Q9Y394-1
DHRS7	NM_001322280.2 link	c.499C>T	p.Leu167Phe	missense_variant	Exon 5 of 7		NP_001309209.1	Q9Y394-2
DHRS7	NM_001322282.2 link	c.409C>T	p.Leu137Phe	missense_variant	Exon 4 of 6		NP_001309211.1
DHRS7	NM_001322281.2 link	c.229C>T	p.Leu77Phe	missense_variant	Exon 5 of 7		NP_001309210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHRS7	ENST00000557185.6 link	c.649C>T	p.Leu217Phe	missense_variant	Exon 5 of 7	1	NM_016029.4	ENSP00000451882.1		Q9Y394-1

Frequencies

GnomAD3 genomes

AF:

0.0000213

AC:

AN:

140610

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000449

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000537

AC:

AN:

186058

Hom.:

AF XY:

0.00

AC XY:

AN XY:

102884

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000422

AC:

AN:

1351208

Hom.:

Cov.:

AF XY:

0.0000329

AC XY:

AN XY:

668482

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000157

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000509

Gnomad4 OTH exome

AF:

0.0000363

GnomAD4 genome

AF:

0.0000213

AC:

AN:

140610

Hom.:

Cov.:

AF XY:

0.0000147

AC XY:

AN XY:

67928

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000449

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000247

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.649C>T (p.L217F) alteration is located in exon 5 (coding exon 5) of the DHRS7 gene. This alteration results from a C to T substitution at nucleotide position 649, causing the leucine (L) at amino acid position 217 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

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D;T;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D;.;D

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

2.9

M;M;.;.

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.7

D;D;.;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0050

D;D;.;D

Sift4G

Uncertain

0.036

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.84

MutPred

0.81

Loss of stability (P = 0.0948);Loss of stability (P = 0.0948);Loss of stability (P = 0.0948);.;

MVP

1.0

MPC

0.31

ClinPred

0.97

GERP RS

5.2

Varity_R

0.48

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over