chr19-1104757-C-T

Variant names:

• chr19-1104757-C-T
• rs919060538
• NM_002085.5:c.85-429C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039848.4(GPX4):​c.23C>T​(p.Ser8Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000071 in 986,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: GPX4 NM_001039848.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.384
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23079893).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039848.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX4	NM_002085.5	MANE Select	c.85-429C>T		intron	N/A	NP_002076.2	P36969-1
	GPX4	NM_001039848.4		c.23C>T	p.Ser8Phe	missense	Exon 1 of 7	NP_001034937.1
	GPX4	NM_001039847.3		c.85-429C>T		intron	N/A	NP_001034936.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX4	ENST00000354171.13	TSL:1 MANE Select	c.85-429C>T		intron	N/A	ENSP00000346103.7	P36969-1
	GPX4	ENST00000611653.4	TSL:1	c.4-429C>T		intron	N/A	ENSP00000483655.1	P36969-2
	GPX4	ENST00000585362.7	TSL:2	c.23C>T	p.Ser8Phe	missense	Exon 1 of 7	ENSP00000473614.3	R4GNE4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151084 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000599 AC: 5 AN: 835068 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 385950

African (AFR) AF: 0.0000632 AC: 1 AN: 15824

American (AMR) AF: 0.00 AC: 0 AN: 998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5170

East Asian (EAS) AF: 0.00 AC: 0 AN: 3650

South Asian (SAS) AF: 0.00 AC: 0 AN: 16488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1628

European-Non Finnish (NFE) AF: 0.00000525 AC: 4 AN: 762604

Other (OTH) AF: 0.00 AC: 0 AN: 27348

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151084 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73762

African (AFR) AF: 0.0000484 AC: 2 AN: 41302

American (AMR) AF: 0.00 AC: 0 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67618

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.0
DANN	Benign	0.93
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.23	T
PhyloP100		-0.38
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.0070	D
Vest4		0.18
MVP		0.73
GERP RS		0.47
PromoterAI		-0.0067	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs919060538; hg19: chr19-1104756;