chr19-1106108-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002085.5(GPX4):c.477-134G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 825,770 control chromosomes in the GnomAD database, including 1,675 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 317 hom., cov: 25)

Exomes 𝑓: 0.050 ( 1358 hom. )

Consequence

GPX4
NM_002085.5 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.721

Publications

3 publications found

Variant links:

Genes affected

GPX4 (HGNC:4556): (glutathione peroxidase 4) The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of hydrogen peroxide, organic hydroperoxides and lipid hydroperoxides, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme has a high preference for lipid hydroperoxides and protects cells against membrane lipid peroxidation and cell death. It is also required for normal sperm development; thus, it has been identified as a 'moonlighting' protein because of its ability to serve dual functions as a peroxidase, as well as a structural protein in mature spermatozoa. Mutations in this gene are associated with Sedaghatian type of spondylometaphyseal dysplasia (SMDS). This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Transcript variants resulting from alternative splicing or use of alternate promoters have been described to encode isoforms with different subcellular localization. [provided by RefSeq, Dec 2018]

GPX4 Gene-Disease associations (from GenCC):

spondylometaphyseal dysplasia, Sedaghatian type
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

GPX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 19-1106108-G-T is Benign according to our data. Variant chr19-1106108-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1321762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GPX4	NM_002085.5	MANE Select	c.477-134G>T	intron	N/A	NP_002076.2
GPX4	NM_001039848.4		c.588-134G>T	intron	N/A	NP_001034937.1
GPX4	NM_001039847.3		c.477-134G>T	intron	N/A	NP_001034936.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
GPX4	ENST00000354171.13	TSL:1 MANE Select	c.477-134G>T	intron	N/A	ENSP00000346103.7
GPX4	ENST00000611653.4	TSL:1	c.396-134G>T	intron	N/A	ENSP00000483655.1
GPX4	ENST00000592940.2	TSL:5	n.714G>T	non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes

AF:

0.0477

AC:

7063

AN:

148042

Hom.:

318

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0121

Gnomad AMI

AF:

0.0385

Gnomad AMR

AF:

0.163

Gnomad ASJ

AF:

0.0494

Gnomad EAS

AF:

0.00160

Gnomad SAS

AF:

0.0336

Gnomad FIN

AF:

0.0285

Gnomad MID

AF:

0.0425

Gnomad NFE

AF:

0.0509

Gnomad OTH

AF:

0.0586

GnomAD4 exome

AF:

0.0501

AC:

33972

AN:

677614

Hom.:

1358

Cov.:

AF XY:

0.0493

AC XY:

17251

AN XY:

349686

show subpopulations

African (AFR)

AF:

0.00968

AC:

167

AN:

17260

American (AMR)

AF:

0.223

AC:

4834

AN:

21704

Ashkenazi Jewish (ASJ)

AF:

0.0522

AC:

787

AN:

15086

East Asian (EAS)

AF:

0.000968

AC:

AN:

33056

South Asian (SAS)

AF:

0.0407

AC:

2176

AN:

53400

European-Finnish (FIN)

AF:

0.0327

AC:

1022

AN:

31254

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

2406

European-Non Finnish (NFE)

AF:

0.0494

AC:

23205

AN:

469916

Other (OTH)

AF:

0.0495

AC:

1659

AN:

33532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1627

3254

4882

6509

8136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

528

1056

1584

2112

2640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0476

AC:

7059

AN:

148156

Hom.:

317

Cov.:

AF XY:

0.0481

AC XY:

3475

AN XY:

72226

show subpopulations

African (AFR)

AF:

0.0121

AC:

488

AN:

40330

American (AMR)

AF:

0.162

AC:

2388

AN:

14698

Ashkenazi Jewish (ASJ)

AF:

0.0494

AC:

169

AN:

3424

East Asian (EAS)

AF:

0.00161

AC:

AN:

4974

South Asian (SAS)

AF:

0.0338

AC:

155

AN:

4582

European-Finnish (FIN)

AF:

0.0285

AC:

294

AN:

10318

Middle Eastern (MID)

AF:

0.0455

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0509

AC:

3392

AN:

66612

Other (OTH)

AF:

0.0576

AC:

118

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

291

582

872

1163

1454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0425

Hom.:

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 12, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.54

(source)

DANN

Benign

0.79

PhyloP100

-0.72

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over