NM_016616.5:c.1007G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016616.5(NME8):c.1007G>A(p.Arg336His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,582,892 control chromosomes in the GnomAD database, including 258 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R336C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 79 hom., cov: 33)

Exomes 𝑓: 0.014 ( 179 hom. )

Consequence

NME8
NM_016616.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.456

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
primary ciliary dyskinesia 6
Inheritance: AR Classification: LIMITED Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

NME8 links:

ENSG00000290149 (HGNC:):

ENSG00000290149 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020843744).

BP6

Variant 7-37884315-G-A is Benign according to our data. Variant chr7-37884315-G-A is described in ClinVar as Benign. ClinVar VariationId is 226853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NME8	NM_016616.5 link	c.1007G>A	p.Arg336His	missense_variant	Exon 13 of 18	ENST00000199447.9	NP_057700.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NME8	ENST00000199447.9 link	c.1007G>A	p.Arg336His	missense_variant	Exon 13 of 18	1	NM_016616.5	ENSP00000199447.4
NME8	ENST00000440017.5 link	c.1007G>A	p.Arg336His	missense_variant	Exon 12 of 16	1		ENSP00000397063.1
ENSG00000290149	ENST00000476620.1 link	c.-38+26970G>A		intron_variant	Intron 2 of 3	4		ENSP00000425858.1
NME8	ENST00000426106.1 link	n.118G>A		non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000408841.1

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3771

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0521

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0143

AC:

3571

AN:

250530

AF XY:

0.0130

show subpopulations

Gnomad AFR exome

AF:

0.0531

Gnomad AMR exome

AF:

0.00881

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.0148

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0138

AC:

19748

AN:

1430830

Hom.:

179

Cov.:

AF XY:

0.0136

AC XY:

9680

AN XY:

713818

show subpopulations

African (AFR)

AF:

0.0514

AC:

1685

AN:

32774

American (AMR)

AF:

0.0103

AC:

460

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

448

AN:

25892

East Asian (EAS)

AF:

0.000304

AC:

AN:

39478

South Asian (SAS)

AF:

0.00173

AC:

148

AN:

85672

European-Finnish (FIN)

AF:

0.0191

AC:

1017

AN:

53372

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.0138

AC:

14935

AN:

1083982

Other (OTH)

AF:

0.0163

AC:

967

AN:

59346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

840

1680

2520

3360

4200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

552

1104

1656

2208

2760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0248

AC:

3774

AN:

152062

Hom.:

Cov.:

AF XY:

0.0243

AC XY:

1804

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0520

AC:

2159

AN:

41482

American (AMR)

AF:

0.0159

AC:

242

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00395

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0182

AC:

192

AN:

10542

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0154

AC:

1050

AN:

67994

Other (OTH)

AF:

0.0175

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

192

384

576

768

960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0166

Hom.:

Bravo

AF:

0.0256

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.0445

AC:

196

ESP6500EA

AF:

0.0157

AC:

135

ExAC

AF:

0.0150

AC:

1824

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.0140

EpiControl

AF:

0.0122

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg336His in exon 13 of TXNDC3: This variant is not expected to have clinical si gnificance because it has been identified in 4.4% (196/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs62001869). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 6

Benign:2

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:1

Dec 28, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Jan 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29177109) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.4

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0068

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00012

LIST_S2

Benign

0.15

.;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L

PhyloP100

0.46

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.89

N;N

REVEL

Benign

0.039

Sift

Benign

0.17

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0020

B;B

Vest4

0.079

MPC

0.023

ClinPred

0.000022

GERP RS

-1.4

Varity_R

0.026

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over