7-37884315-G-C

Position:

chr7-37884315-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016616.5(NME8):c.1007G>C(p.Arg336Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000884 in 1,583,354 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R336H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

NME8
NM_016616.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.456

Variant links:

Genes affected

NME8 (HGNC:16473): (NME/NM23 family member 8) This gene encodes a protein with an N-terminal thioredoxin domain and three C-terminal nucleoside diphosphate kinase (NDK) domains, but the NDK domains are thought to be catalytically inactive. The sea urchin ortholog of this gene encodes a component of sperm outer dynein arms, and the protein is implicated in ciliary function. Mutations in this gene are implicated in primary ciliary dyskinesia type 6.[provided by RefSeq, Nov 2009]

NME8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.08098492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NME8	NM_016616.5 linkuse as main transcript	c.1007G>C	p.Arg336Pro	missense_variant	13/18	ENST00000199447.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NME8	ENST00000199447.9 linkuse as main transcript	c.1007G>C	p.Arg336Pro	missense_variant	13/18	1	NM_016616.5	P1
NME8	ENST00000440017.5 linkuse as main transcript	c.1007G>C	p.Arg336Pro	missense_variant	12/16	1		P1
NME8	ENST00000426106.1 linkuse as main transcript	c.118G>C	p.Val40Leu	missense_variant, NMD_transcript_variant	3/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250530

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000869

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000699

AC:

AN:

1431402

Hom.:

Cov.:

AF XY:

0.00000700

AC XY:

AN XY:

714086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.0000672

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:

0.00000369

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151952

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74188

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.00

Gnomad4 OTH

AF:

0.000479

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2021

ClinVar contains an entry for this variant (Variation ID: 567173). This variant has not been reported in the literature in individuals affected with NME8-related conditions. This variant is present in population databases (rs62001869, ExAC 0.02%). This sequence change replaces arginine with proline at codon 336 of the NME8 protein (p.Arg336Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.1

DANN

Benign

0.51

DEOGEN2

Benign

0.075

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.050

M_CAP

Benign

0.030

MetaRNN

Benign

0.081

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.12

Sift

Benign

0.17

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.21

B;B

Vest4

0.25

MutPred

0.39

Loss of ubiquitination at K331 (P = 0.0456);Loss of ubiquitination at K331 (P = 0.0456);

MVP

0.32

MPC

0.054

ClinPred

0.082

GERP RS

-1.4

Varity_R

0.40

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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