chr7-26183723-C-T

Position:

• chr7-26183723-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004289.7(NFE2L3):​c.773C>T​(p.Thr258Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NFE2L3 NM_004289.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.542

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]

HNRNPA2B1 (HGNC:5033): (heterogeneous nuclear ribonucleoprotein A2/B1) This gene belongs to the A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has two repeats of quasi-RRM domains that bind to RNAs. This gene has been described to generate two alternatively spliced transcript variants which encode different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0410046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFE2L3	NM_004289.7	c.773C>T	p.Thr258Ile	missense_variant	3/4	ENST00000056233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFE2L3	ENST00000056233.4	c.773C>T	p.Thr258Ile	missense_variant	3/4	1	NM_004289.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459984 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726442

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.773C>T (p.T258I) alteration is located in exon 3 (coding exon 3) of the NFE2L3 gene. This alteration results from a C to T substitution at nucleotide position 773, causing the threonine (T) at amino acid position 258 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N;.
REVEL	Benign	0.035
Sift	Benign	0.067	T;.
Sift4G	Benign	0.098	T;T
Polyphen		0.0040	B;.
Vest4		0.32
MutPred		0.10		Loss of phosphorylation at T258 (P = 0.1169);.;
MVP		0.16
MPC		0.0010
ClinPred		0.043	T
GERP RS		2.9
Varity_R		0.057
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs755242482; hg19: chr7-26223343;