chr19-1104439-G-C

Variant names:

• chr19-1104439-G-C
• rs2074450
• NM_002085.5:c.84+312G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002085.5(GPX4):​c.84+312G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 377,856 control chromosomes in the GnomAD database, including 1,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (413 hom., cov: 33)
  • Exomes 𝑓: 0.060 (842 hom.)
• Consequence: GPX4 NM_002085.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00100
• 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), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-1104439-G-C is Benign according to our data. Variant chr19-1104439-G-C is described in ClinVar as Benign. ClinVar VariationId is 1174251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.238 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPX4	NM_002085.5	MANE Select	c.84+312G>C		intron	N/A	NP_002076.2	P36969-1
	GPX4	NM_001039847.3		c.84+312G>C		intron	N/A	NP_001034936.1
	GPX4	NM_001367832.1		c.3+312G>C		intron	N/A	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.84+312G>C		intron	N/A	ENSP00000346103.7	P36969-1
	GPX4	ENST00000611653.4	TSL:1	c.3+312G>C		intron	N/A	ENSP00000483655.1	P36969-2
	GPX4	ENST00000593032.6	TSL:3	c.3+312G>C		intron	N/A	ENSP00000465828.4	K7EKX7

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7830 AN: 151992 Hom.: 412 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0553

Gnomad OTH AF: 0.0602

GnomAD4 exome AF: 0.0601 AC: 13558 AN: 225756 Hom.: 842 Cov.: 5 AF XY: 0.0601 AC XY: 6781 AN XY: 112918

African (AFR) AF: 0.0101 AC: 60 AN: 5940

American (AMR) AF: 0.0251 AC: 112 AN: 4470

Ashkenazi Jewish (ASJ) AF: 0.0403 AC: 281 AN: 6968

East Asian (EAS) AF: 0.232 AC: 3334 AN: 14378

South Asian (SAS) AF: 0.121 AC: 747 AN: 6178

European-Finnish (FIN) AF: 0.0372 AC: 528 AN: 14176

Middle Eastern (MID) AF: 0.0349 AC: 37 AN: 1060

European-Non Finnish (NFE) AF: 0.0486 AC: 7753 AN: 159520

Other (OTH) AF: 0.0540 AC: 706 AN: 13066

GnomAD4 genome AF: 0.0515 AC: 7836 AN: 152100 Hom.: 413 Cov.: 33 AF XY: 0.0555 AC XY: 4128 AN XY: 74362

African (AFR) AF: 0.0115 AC: 479 AN: 41542

American (AMR) AF: 0.0424 AC: 648 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 154 AN: 3472

East Asian (EAS) AF: 0.250 AC: 1282 AN: 5138

South Asian (SAS) AF: 0.163 AC: 784 AN: 4824

European-Finnish (FIN) AF: 0.0513 AC: 543 AN: 10576

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0553 AC: 3757 AN: 67946

Other (OTH) AF: 0.0629 AC: 133 AN: 2114

Alfa AF: 0.0519 Hom.: 30

Bravo AF: 0.0458

Asia WGS AF: 0.182 AC: 624 AN: 3436

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		-0.0010
PromoterAI		-0.0023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2074450; hg19: chr19-1104438;