19-3941130-T-G

Position:

• chr19-3941130-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170678.3(NMRK2):​c.455T>G​(p.Met152Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NMRK2 NM_170678.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

Genes affected

NMRK2 (HGNC:17871): (nicotinamide riboside kinase 2) Enables ribosylnicotinamide kinase activity and ribosylnicotinate kinase activity. Predicted to be involved in NAD metabolic process. Predicted to act upstream of or within negative regulation of myoblast differentiation. Located in nucleoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000289254 (HGNC:):

ACMG classification

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, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMRK2	NM_170678.3	c.455T>G	p.Met152Arg	missense_variant	7/8	ENST00000168977.7	NP_733778.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NMRK2	ENST00000168977.7	c.455T>G	p.Met152Arg	missense_variant	7/8	2	NM_170678.3	ENSP00000168977.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Aug 11, 2022

The c.455T>G (p.M152R) alteration is located in exon 7 (coding exon 6) of the NMRK2 gene. This alteration results from a T to G substitution at nucleotide position 455, causing the methionine (M) at amino acid position 152 to be replaced by an arginine (R). 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	0.60
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.21	.;T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.1	.;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0060	.;D;.
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.90
MutPred		0.73		.;Loss of ubiquitination at K155 (P = 0.0709);.;
MVP		0.53
MPC		0.40
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.85
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: chr19-3941128;