ENST00000611653.4:c.-46G>T

Variant names:

• chr19-1104079-G-T
• rs4807542
• ENST00000611653.4:c.-46G>T

Variant summary

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

The ENST00000611653.4(GPX4):​c.-46G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000264 in 1,517,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GPX4 ENST00000611653.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 54 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), G2P, Ambry Genetics, Orphanet

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 (BayesDel_noAF=-0.34).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000611653.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX4	NM_002085.5	MANE Select	c.36G>T	p.Pro12Pro	synonymous	Exon 1 of 7	NP_002076.2
	GPX4	NM_001367832.1		c.-46G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001354761.1
	GPX4	NM_001039847.3		c.36G>T	p.Pro12Pro	synonymous	Exon 1 of 7	NP_001034936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX4	ENST00000611653.4	TSL:1	c.-46G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000483655.1
	GPX4	ENST00000354171.13	TSL:1 MANE Select	c.36G>T	p.Pro12Pro	synonymous	Exon 1 of 7	ENSP00000346103.7
	GPX4	ENST00000611653.4	TSL:1	c.-46G>T		5_prime_UTR	Exon 1 of 7	ENSP00000483655.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 34

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000220 AC: 3 AN: 1365692 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 673680

African (AFR) AF: 0.0000348 AC: 1 AN: 28736

American (AMR) AF: 0.00 AC: 0 AN: 34678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24536

East Asian (EAS) AF: 0.00 AC: 0 AN: 33140

South Asian (SAS) AF: 0.00 AC: 0 AN: 77392

European-Finnish (FIN) AF: 0.0000288 AC: 1 AN: 34700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4028

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1071494

Other (OTH) AF: 0.00 AC: 0 AN: 56988

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 2645

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.6
DANN	Benign	0.90
PhyloP100		-1.6
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs4807542; hg19: chr19-1104078;