rs1057519923

Positions:

• chr2-177234081-T-A
• chr2-177234081-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_006164.5(NFE2L2):​c.236A>T​(p.Glu79Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E79D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NFE2L2 NM_006164.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:6
• Conservation: PhyloP100: 7.67

Genes affected

NFE2L2 (HGNC:7782): (NFE2 like bZIP transcription factor 2) This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_006164.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-177234080-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376468.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 2-177234081-T-A is Pathogenic according to our data. Variant chr2-177234081-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376467.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFE2L2	NM_006164.5	c.236A>T	p.Glu79Val	missense_variant	2/5	ENST00000397062.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFE2L2	ENST00000397062.8	c.236A>T	p.Glu79Val	missense_variant	2/5	1	NM_006164.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: no assertion criteria provided

Submissions by phenotype

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of uterine cervix Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Uncertain	0.98
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.7	D;D;D;.;N;D;.;D;D;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D;.;D;D;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.;D;.
Vest4		0.71
MutPred		0.31		.;Loss of disorder (P = 0.0362);.;.;.;.;.;.;.;.;
MVP		0.61
MPC		0.70
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057519923; hg19: chr2-178098809; COSMIC: COSV67960135; COSMIC: COSV67960135;