7-26185116-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004289.7(NFE2L3):c.1418G>C(p.Ser473Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,894 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S473N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 20 hom. )

Consequence

NFE2L3
NM_004289.7 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.474

Publications

4 publications found

Variant links:

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]

NFE2L3 links:

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]

HNRNPA2B1 Gene-Disease associations (from GenCC):

inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
oculopharyngeal muscular dystrophy 2
Inheritance: AD Classification: STRONG Submitted by: G2P
amyotrophic lateral sclerosis
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, ClinGen
inclusion body myopathy with Paget disease of bone and frontotemporal dementia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HNRNPA2B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036691427).

BP6

Variant 7-26185116-G-C is Benign according to our data. Variant chr7-26185116-G-C is described in ClinVar as [Benign]. Clinvar id is 2657355.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00173 (2534/1461598) while in subpopulation MID AF = 0.0217 (125/5762). AF 95% confidence interval is 0.0186. There are 20 homozygotes in GnomAdExome4. There are 1290 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L3	NM_004289.7 link	c.1418G>C	p.Ser473Thr	missense_variant	Exon 4 of 4	ENST00000056233.4	NP_004280.5	Q9Y4A8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFE2L3	ENST00000056233.4 link	c.1418G>C	p.Ser473Thr	missense_variant	Exon 4 of 4	1	NM_004289.7	ENSP00000056233.3		Q9Y4A8

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

275

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00575

GnomAD2 exomes

AF:

0.00286

AC:

719

AN:

251120

AF XY:

0.00290

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.0342

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00181

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00173

AC:

2534

AN:

1461598

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

1290

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33472

American (AMR)

AF:

0.00255

AC:

114

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

916

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00144

AC:

124

AN:

86242

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.0217

AC:

125

AN:

5762

European-Non Finnish (NFE)

AF:

0.000833

AC:

926

AN:

1111812

Other (OTH)

AF:

0.00520

AC:

314

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

162

323

485

646

808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00180

AC:

274

AN:

152296

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41554

American (AMR)

AF:

0.00222

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

68022

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00514

Hom.:

Bravo

AF:

0.00217

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00223

AC:

271

EpiCase

AF:

0.00327

EpiControl

AF:

0.00296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HNRNPA2B1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.089

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.080

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.33

M_CAP

Benign

0.0056

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.5

PhyloP100

-0.47

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.7

REVEL

Benign

0.027

Sift

Benign

0.091

Sift4G

Benign

0.39

Polyphen

0.0010

Vest4

0.085

MVP

0.34

MPC

0.0012

ClinPred

0.0069

GERP RS

1.5

Varity_R

0.072

gMVP

0.15

Mutation Taster

=99/1

polymorphism

(source)

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

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7-26185116-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over