Genetic Variant NM_001509.3:c.445T>C (chr6-28532406-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001509.3(GPX5):c.445T>C(p.Phe149Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GPX5
NM_001509.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08

Publications

0 publications found

Variant links:

Genes affected

GPX5 (HGNC:4557): (glutathione peroxidase 5) This gene belongs to the glutathione peroxidase family. It is specifically expressed in the epididymis in the mammalian male reproductive tract, and is androgen-regulated. Unlike several other characterized glutathione peroxidases, this enzyme is not a selenoprotein, lacking the selenocysteine residue. Thus, it is selenium-independent, and has been proposed to play a role in protecting the membranes of spermatozoa from the damaging effects of lipid peroxidation and/or preventing premature acrosome reaction. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2016]

GPX5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001509.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPX5	NM_001509.3	MANE Select	c.445T>C	p.Phe149Leu	missense	Exon 4 of 5	NP_001500.1	O75715-1
GPX5	NM_003996.3		c.*24T>C		3_prime_UTR	Exon 3 of 4	NP_003987.2	O75715-2
GPX5	NR_144470.2		n.523T>C		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPX5	ENST00000412168.7	TSL:1 MANE Select	c.445T>C	p.Phe149Leu	missense	Exon 4 of 5	ENSP00000392398.2	O75715-1
GPX5	ENST00000469384.1	TSL:1	c.*24T>C		3_prime_UTR	Exon 3 of 4	ENSP00000419935.1	O75715-2
GPX5	ENST00000442674.6	TSL:5	n.820T>C		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000442

AC:

AN:

226096

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000359

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1431676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712138

African (AFR)

AF:

0.00

AC:

AN:

31428

American (AMR)

AF:

0.00

AC:

AN:

38898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25348

East Asian (EAS)

AF:

0.00

AC:

AN:

37988

South Asian (SAS)

AF:

0.00

AC:

AN:

81102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098784

Other (OTH)

AF:

0.00

AC:

AN:

59202

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

3.4

PhyloP100

7.1

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.38

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

0.99

Vest4

0.78

MutPred

0.81

Loss of catalytic residue at F149 (P = 0.0109)

MVP

0.31

MPC

0.60

ClinPred

0.99

GERP RS

4.2

Varity_R

0.77

gMVP

0.71

Mutation Taster

=53/47

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over