Variant 16-4469381-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020677.6(NMRAL1):c.125A>C(p.Lys42Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000911 in 1,614,128 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00074 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00093 ( 2 hom. )

Consequence

NMRAL1
NM_020677.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0970

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]

NMRAL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008740604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NMRAL1	NM_020677.6 linkuse as main transcript	c.125A>C	p.Lys42Thr	missense_variant	3/6	ENST00000283429.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NMRAL1	ENST00000283429.11 linkuse as main transcript	c.125A>C	p.Lys42Thr	missense_variant	3/6	1	NM_020677.6	P1

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.00131

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000851

AC:

214

AN:

251488

Hom.:

AF XY:

0.000846

AC XY:

115

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000929

AC:

1358

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000936

AC XY:

681

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152290

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00131

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000914

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.000873

AC:

106

EpiCase

AF:

0.00196

EpiControl

AF:

0.00213

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 submitter

clinical testing

Ambry Genetics

Sep 15, 2021

The c.125A>C (p.K42T) alteration is located in exon 3 (coding exon 2) of the NMRAL1 gene. This alteration results from a A to C substitution at nucleotide position 125, causing the lysine (K) at amino acid position 42 to be replaced by a threonine (T). 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

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.58

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.015

T;T;T;T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.14

M_CAP

Benign

0.021

MetaRNN

Benign

0.0087

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;L;L;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.82

N;.;N;.;.

REVEL

Benign

0.036

Sift

Benign

0.47

T;.;T;.;.

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.076

B;B;B;B;.

Vest4

0.29

MVP

0.33

MPC

0.050

ClinPred

0.0083

GERP RS

-3.3

Varity_R

0.13

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over