7-26184630-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004289.7(NFE2L3):c.932A>G(p.Gln311Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00557 in 1,613,964 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (21 hom.)
• Consequence: NFE2L3 NM_004289.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 5.51

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008880228).
• BP6: Variant 7-26184630-A-G is Benign according to our data. Variant chr7-26184630-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2498230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFE2L3	NM_004289.7	c.932A>G	p.Gln311Arg	missense_variant	4/4	ENST00000056233.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFE2L3	ENST00000056233.4	c.932A>G	p.Gln311Arg	missense_variant	4/4	1	NM_004289.7	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152230 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00564

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00314 AC: 789 AN: 251006 Hom.: 3 AF XY: 0.00325 AC XY: 441 AN XY: 135648

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00602

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00584 AC: 8533 AN: 1461616 Hom.: 21 Cov.: 32 AF XY: 0.00565 AC XY: 4105 AN XY: 727116

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00727

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.00297 AC: 453 AN: 152348 Hom.: 2 Cov.: 32 AF XY: 0.00287 AC XY: 214 AN XY: 74510

Gnomad4 AFR AF: 0.000697

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00564

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00478 Hom.: 4

Bravo AF: 0.00295

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00311 AC: 378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Keratoconus Uncertain:1

Uncertain significance, no assertion criteria provided

research

Institute of Human Genetics, Polish Academy of Sciences

Apr 01, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

NFE2L3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.089
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.91	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.022	D
Polyphen		0.31	B
Vest4		0.091
MVP		0.45
MPC		0.0011
ClinPred		0.017	T
GERP RS		5.1
Varity_R		0.21
gMVP		0.32

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: rs148235978; hg19: chr7-26224250; COSMIC: COSV105022808; COSMIC: COSV105022808;