rs540807904

Variant names:

• chr19-1104059-C-G
• rs540807904
• NM_002085.5:c.16C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-1104059-C-G
• chr19-1104059-C-T

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.16C>G​(p.Leu6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,367,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L6F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GPX4 NM_002085.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.464
• 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=0.08944264).

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.16C>G	p.Leu6Val	missense	Exon 1 of 7	NP_002076.2	P36969-1
	GPX4	NM_001039847.3		c.16C>G	p.Leu6Val	missense	Exon 1 of 7	NP_001034936.1
	GPX4	NM_001367832.1		c.-66C>G		5_prime_UTR	Exon 1 of 7	NP_001354761.1	P36969-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX4	ENST00000354171.13	TSL:1 MANE Select	c.16C>G	p.Leu6Val	missense	Exon 1 of 7	ENSP00000346103.7	P36969-1
	GPX4	ENST00000611653.4	TSL:1	c.-66C>G		5_prime_UTR	Exon 1 of 7	ENSP00000483655.1	P36969-2
	GPX4	ENST00000706713.1		c.16C>G	p.Leu6Val	missense	Exon 1 of 7	ENSP00000516510.1	A0A9L9PXS3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1367308 Hom.: 0 Cov.: 30 AF XY: 0.00000296 AC XY: 2 AN XY: 674594

African (AFR) AF: 0.0000346 AC: 1 AN: 28880

American (AMR) AF: 0.00 AC: 0 AN: 34802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24608

East Asian (EAS) AF: 0.00 AC: 0 AN: 33382

South Asian (SAS) AF: 0.00 AC: 0 AN: 77558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4032

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1072094

Other (OTH) AF: 0.00 AC: 0 AN: 57056

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.46
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.057
Sift	Uncertain	0.026	D
Sift4G	Benign	0.47	T
Polyphen		0.88	P
Vest4		0.22
MutPred		0.44		Loss of disorder (P = 0.0356)
MVP		0.22
MPC		0.11
ClinPred		0.26	T
GERP RS		0.034
PromoterAI		-0.15	Neutral
Varity_R		0.066
Mutation Taster		=95/5	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: rs540807904; hg19: chr19-1104058;