16-4466168-T-G

Position:

• chr16-4466168-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020677.6(NMRAL1):​c.514A>C​(p.Lys172Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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: 0.957

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0830259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMRAL1	NM_020677.6	c.514A>C	p.Lys172Gln	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.514A>C	p.Lys172Gln	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

Nov 25, 2024

The c.514A>C (p.K172Q) alteration is located in exon 4 (coding exon 3) of the NMRAL1 gene. This alteration results from a A to C substitution at nucleotide position 514, causing the lysine (K) at amino acid position 172 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	Benign	0.098
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.0093	T;T;T;T;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.71	.;.;T;.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.083	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.;L;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.18	N;.;.;N;.;.
REVEL	Benign	0.014
Sift	Benign	0.51	T;.;.;T;.;.
Sift4G	Benign	0.46	T;T;T;T;T;T
Polyphen		0.032	B;B;.;B;B;.
Vest4		0.35
MutPred		0.40		Loss of ubiquitination at K172 (P = 0.0174);Loss of ubiquitination at K172 (P = 0.0174);.;Loss of ubiquitination at K172 (P = 0.0174);Loss of ubiquitination at K172 (P = 0.0174);.;
MVP		0.28
MPC		0.033
ClinPred		0.082	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-4516169;