16-4466320-G-T

Position:

• chr16-4466320-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020677.6(NMRAL1):​c.362C>A​(p.Thr121Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 4.20

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMRAL1	NM_020677.6	c.362C>A	p.Thr121Lys	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.362C>A	p.Thr121Lys	missense_variant	4/6	1	NM_020677.6	ENSP00000283429.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 21, 2024

The c.362C>A (p.T121K) 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 362, causing the threonine (T) at amino acid position 121 to be replaced by a lysine (K). 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	0.72
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;T;T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	.;.;T;.;T;T
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.0	D;.;.;D;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.011	D;.;.;D;.;.
Sift4G	Uncertain	0.044	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;.
Vest4		0.59
MutPred		0.58		Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);.;Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);.;
MVP		0.59
MPC		0.26
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.85
gMVP		0.68

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

Other links and lift over

dbSNP: rs779258307; hg19: chr16-4516321;