chr12-54292754-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001136023.3(NFE2):ā€‹c.742G>Cā€‹(p.Asp248His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

NFE2
NM_001136023.3 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
NFE2 (HGNC:7780): (nuclear factor, erythroid 2) Enables several functions, including WW domain binding activity; identical protein binding activity; and protein N-terminus binding activity. Contributes to cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including labyrinthine layer blood vessel development; negative regulation of bone mineralization; and negative regulation of syncytium formation by plasma membrane fusion. Part of protein-DNA complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NFE2NM_001136023.3 linkuse as main transcriptc.742G>C p.Asp248His missense_variant 3/3 ENST00000435572.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NFE2ENST00000435572.7 linkuse as main transcriptc.742G>C p.Asp248His missense_variant 3/31 NM_001136023.3 P1
ENST00000553061.1 linkuse as main transcriptn.545+15579C>G intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 09, 2022The c.742G>C (p.D248H) alteration is located in exon 3 (coding exon 2) of the NFE2 gene. This alteration results from a G to C substitution at nucleotide position 742, causing the aspartic acid (D) at amino acid position 248 to be replaced by a histidine (H). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;D;D;D;D
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
.;.;.;D;D
M_CAP
Uncertain
0.091
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Pathogenic
3.0
M;M;M;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-5.0
D;D;D;D;D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0040
D;D;D;D;D
Sift4G
Uncertain
0.0050
D;D;D;D;.
Polyphen
1.0
D;D;D;D;.
Vest4
0.69
MutPred
0.31
Gain of catalytic residue at N244 (P = 2e-04);Gain of catalytic residue at N244 (P = 2e-04);Gain of catalytic residue at N244 (P = 2e-04);Gain of catalytic residue at N244 (P = 2e-04);Gain of catalytic residue at N244 (P = 2e-04);
MVP
0.95
MPC
1.5
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.65
gMVP
0.86

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767181165; hg19: chr12-54686538; API