NM_002085.5:c.85-429C>A

Variant names:

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

Variant summary

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

The NM_002085.5(GPX4):​c.85-429C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 835,068 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GPX4 NM_002085.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.384
• Publications: 0 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=0.23766941).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX4	NM_002085.5	MANE Select	c.85-429C>A		intron	N/A	NP_002076.2	P36969-1
	GPX4	NM_001039848.4		c.23C>A	p.Ser8Tyr	missense	Exon 1 of 7	NP_001034937.1
	GPX4	NM_001039847.3		c.85-429C>A		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>A		intron	N/A	ENSP00000346103.7	P36969-1
	GPX4	ENST00000611653.4	TSL:1	c.4-429C>A		intron	N/A	ENSP00000483655.1	P36969-2
	GPX4	ENST00000585362.7	TSL:2	c.23C>A	p.Ser8Tyr	missense	Exon 1 of 7	ENSP00000473614.3	R4GNE4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 4 AN: 835068 Hom.: 0 Cov.: 30 AF XY: 0.00000259 AC XY: 1 AN XY: 385950

African (AFR) AF: 0.00 AC: 0 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 Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.1
DANN	Benign	0.73
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.24	T
PhyloP100		-0.38
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.010	D
Vest4		0.15
MVP		0.73
GERP RS		0.47
PromoterAI		-0.023	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)		0.010		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;