Variant 19-3939915-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_170678.3(NMRK2):c.339G>C(p.Leu113Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NMRK2
NM_170678.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0740

Variant links:

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]

NMRK2 links:

ENSG00000289254 (HGNC:):

ENSG00000289254 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.33075786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NMRK2	NM_170678.3 linkuse as main transcript	c.339G>C	p.Leu113Phe	missense_variant	6/8	ENST00000168977.7	NP_733778.1	Q9NPI5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NMRK2	ENST00000168977.7 linkuse as main transcript	c.339G>C	p.Leu113Phe	missense_variant	6/8	2	NM_170678.3	ENSP00000168977.1		Q9NPI5-1

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249776

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461212

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726910

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73880

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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 14, 2021

The c.339G>C (p.L113F) alteration is located in exon 6 (coding exon 5) of the NMRK2 gene. This alteration results from a G to C substitution at nucleotide position 339, causing the leucine (L) at amino acid position 113 to be replaced by a phenylalanine (F). 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

0.17

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;T;.

Eigen

Benign

0.11

Eigen_PC

Benign

-0.0071

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.63

T;T;.

M_CAP

Benign

0.0055

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

.;M;.

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.6

.;D;.

REVEL

Benign

0.20

Sift

Uncertain

0.0060

.;D;.

Sift4G

Uncertain

0.022

D;D;D

Polyphen

0.92

.;P;.

Vest4

0.36

MutPred

0.52

.;Loss of ubiquitination at K108 (P = 0.0962);.;

MVP

0.48

MPC

0.27

ClinPred

0.76

GERP RS

-0.36

Varity_R

0.23

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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