16-4466295-G-T

Variant summary

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

The NM_020677.6(NMRAL1):​c.387C>A​(p.His129Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,954 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 (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

NMRAL1
NM_020677.6 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.30
Variant links:
Genes affected
NMRAL1 (HGNC:24987): (NmrA like redox sensor 1) This gene encodes an NADPH sensor protein that preferentially binds to NADPH. The encoded protein also negatively regulates the activity of NF-kappaB in a ubiquitylation-dependent manner. It plays a key role in cellular antiviral response by negatively regulating the interferon response factor 3-mediated expression of interferon beta. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Feb 2015]

Genome browser will be placed here

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, 0.865

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NMRAL1NM_020677.6 linkc.387C>A p.His129Gln missense_variant 4/6 ENST00000283429.11 NP_065728.1 Q9HBL8A0A384P622

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NMRAL1ENST00000283429.11 linkc.387C>A p.His129Gln missense_variant 4/61 NM_020677.6 ENSP00000283429.6 Q9HBL8

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251094
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135790
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461788
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000986
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000165
AC:
2

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 GeneticsNov 24, 2024The c.387C>A (p.H129Q) alteration is located in exon 4 (coding exon 3) of the NMRAL1 gene. This alteration results from a C to A substitution at nucleotide position 387, causing the histidine (H) at amino acid position 129 to be replaced by a glutamine (Q). 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
0.91
BayesDel_addAF
Uncertain
0.073
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T;T;T;T;T;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.85
.;.;T;.;D;T
M_CAP
Benign
0.039
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Pathogenic
3.7
H;H;.;H;H;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-7.1
D;.;.;D;.;.
REVEL
Uncertain
0.51
Sift
Uncertain
0.0020
D;.;.;D;.;.
Sift4G
Benign
0.096
T;T;D;T;T;T
Polyphen
1.0
D;D;.;D;D;.
Vest4
0.87
MutPred
0.86
Loss of methylation at R124 (P = 0.1109);Loss of methylation at R124 (P = 0.1109);.;Loss of methylation at R124 (P = 0.1109);Loss of methylation at R124 (P = 0.1109);.;
MVP
0.56
MPC
0.25
ClinPred
0.98
D
GERP RS
5.8
Varity_R
0.94
gMVP
0.71

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: rs776130933; hg19: chr16-4516296; API