chr19-1106478-G-C

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.561+19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,612,450 control chromosomes in the GnomAD database, including 48,695 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5387 hom., cov: 32)

Exomes 𝑓: 0.24 ( 43308 hom. )

Consequence

GPX4
NM_002085.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.485

Publications

28 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), Ambry Genetics, Orphanet, G2P

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=-0.86).

BP6

Variant 19-1106478-G-C is Benign according to our data. Variant chr19-1106478-G-C is described in ClinVar as Benign. ClinVar VariationId is 1598938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.331 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	UniProt
GPX4	NM_002085.5	MANE Select	c.561+19G>C	intron	N/A	NP_002076.2	P36969-1
GPX4	NM_001039848.4		c.672+19G>C	intron	N/A	NP_001034937.1
GPX4	NM_001039847.3		c.583+19G>C	intron	N/A	NP_001034936.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GPX4	ENST00000354171.13	TSL:1 MANE Select	c.561+19G>C	intron	N/A	ENSP00000346103.7	P36969-1
GPX4	ENST00000611653.4	TSL:1	c.480+19G>C	intron	N/A	ENSP00000483655.1	P36969-2
GPX4	ENST00000593032.6	TSL:3	c.541+19G>C	intron	N/A	ENSP00000465828.4	K7EKX7

Frequencies

GnomAD3 genomes

AF:

0.263

AC:

39885

AN:

151882

Hom.:

5382

Cov.:

show subpopulations

Gnomad AFR

AF:

0.286

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.339

Gnomad ASJ

AF:

0.267

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.215

Gnomad FIN

AF:

0.288

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.240

Gnomad OTH

AF:

0.271

GnomAD2 exomes

AF:

0.259

AC:

64418

AN:

248622

AF XY:

0.252

show subpopulations

Gnomad AFR exome

AF:

0.284

Gnomad AMR exome

AF:

0.378

Gnomad ASJ exome

AF:

0.267

Gnomad EAS exome

AF:

0.131

Gnomad FIN exome

AF:

0.271

Gnomad NFE exome

AF:

0.246

Gnomad OTH exome

AF:

0.244

GnomAD4 exome

AF:

0.240

AC:

350002

AN:

1460450

Hom.:

43308

Cov.:

AF XY:

0.239

AC XY:

173734

AN XY:

726580

show subpopulations

African (AFR)

AF:

0.283

AC:

9472

AN:

33464

American (AMR)

AF:

0.372

AC:

16620

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6980

AN:

26106

East Asian (EAS)

AF:

0.161

AC:

6379

AN:

39686

South Asian (SAS)

AF:

0.224

AC:

19309

AN:

86248

European-Finnish (FIN)

AF:

0.268

AC:

14147

AN:

52878

Middle Eastern (MID)

AF:

0.253

AC:

1460

AN:

5766

European-Non Finnish (NFE)

AF:

0.236

AC:

261841

AN:

1111260

Other (OTH)

AF:

0.229

AC:

13794

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

15714

31427

47141

62854

78568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8948

17896

26844

35792

44740

<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:

0.263

AC:

39915

AN:

152000

Hom.:

5387

Cov.:

AF XY:

0.265

AC XY:

19676

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.286

AC:

11865

AN:

41436

American (AMR)

AF:

0.338

AC:

5172

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

927

AN:

3470

East Asian (EAS)

AF:

0.129

AC:

668

AN:

5172

South Asian (SAS)

AF:

0.215

AC:

1038

AN:

4828

European-Finnish (FIN)

AF:

0.288

AC:

3044

AN:

10582

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.240

AC:

16304

AN:

67910

Other (OTH)

AF:

0.268

AC:

564

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1536

3072

4609

6145

7681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

402

804

1206

1608

2010

<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:

0.174

Hom.:

517

Bravo

AF:

0.266

Asia WGS

AF:

0.191

AC:

665

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.1

(source)

DANN

Benign

0.58

PhyloP100

0.48

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over