7-26152899-C-G

Variant names:

• chr7-26152899-C-G
• rs1180670857
• NM_004289.7:c.401C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004289.7(NFE2L3):​c.401C>G​(p.Ser134Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,296,970 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S134L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: NFE2L3 NM_004289.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.298
• Publications: 0 publications found

Genes affected

NFE2L3 (HGNC:7783): (NFE2 like bZIP transcription factor 3) This gene encodes a member of the cap 'n' collar basic-region leucine zipper family of transcription factors. The encoded protein heterodimerizes with small musculoaponeurotic fibrosarcoma factors to bind antioxidant response elements in target genes. This protein is a membrane bound glycoprotein that is targeted to the endoplasmic reticulum and the nuclear envelope. Pseudogenes of this gene are found on chromosomes 16, 17, and 18. [provided by RefSeq, Mar 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33753896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L3	NM_004289.7	c.401C>G	p.Ser134Trp	missense_variant	Exon 1 of 4	ENST00000056233.4	NP_004280.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFE2L3	ENST00000056233.4	c.401C>G	p.Ser134Trp	missense_variant	Exon 1 of 4	1	NM_004289.7	ENSP00000056233.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1296970 Hom.: 0 Cov.: 31 AF XY: 0.00000157 AC XY: 1 AN XY: 638458

African (AFR) AF: 0.00 AC: 0 AN: 25740

American (AMR) AF: 0.00 AC: 0 AN: 19954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21722

East Asian (EAS) AF: 0.00 AC: 0 AN: 28306

South Asian (SAS) AF: 0.00 AC: 0 AN: 67678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3824

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1043708

Other (OTH) AF: 0.00 AC: 0 AN: 53754

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.30
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.28	B
Vest4		0.38
MutPred		0.36		Loss of glycosylation at S134 (P = 0.0022);
MVP		0.48
MPC		2.3
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.15
gMVP		0.31
Mutation Taster		=77/23	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: rs1180670857; hg19: chr7-26192519;