16-4466281-C-G

Position:

• chr16-4466281-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020677.6(NMRAL1):​c.401G>C​(p.Gly134Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NMRAL1 NM_020677.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.422002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMRAL1	NM_020677.6	c.401G>C	p.Gly134Ala	missense_variant	4/6	ENST00000283429.11	NP_065728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NMRAL1	ENST00000283429.11	c.401G>C	p.Gly134Ala	missense_variant	4/6	1	NM_020677.6	ENSP00000283429.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

The c.401G>C (p.G134A) alteration is located in exon 4 (coding exon 3) of the NMRAL1 gene. This alteration results from a G to C substitution at nucleotide position 401, causing the glycine (G) at amino acid position 134 to be replaced by an alanine (A). 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	0.31
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T;T;T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	.;.;D;.;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.42	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L;.;L;L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.4	N;.;.;N;.;.
REVEL	Uncertain	0.29
Sift	Benign	0.41	T;.;.;T;.;.
Sift4G	Benign	0.58	T;T;D;T;T;T
Polyphen		1.0	D;D;.;D;D;.
Vest4		0.68
MutPred		0.53		Loss of ubiquitination at K133 (P = 0.0877);Loss of ubiquitination at K133 (P = 0.0877);.;Loss of ubiquitination at K133 (P = 0.0877);Loss of ubiquitination at K133 (P = 0.0877);.;
MVP		0.34
MPC		0.25
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.63
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-4516282;