rs62001870

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.1013T>C(p.Ile338Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0493 in 1,588,014 control chromosomes in the GnomAD database, including 2,212 homozygotes. In-silico tool predicts 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. I338F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.036 ( 135 hom., cov: 32)

Exomes 𝑓: 0.051 ( 2077 hom. )

Consequence

NME8
NM_016616.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.49

Publications

13 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=0.0035468638).

BP6

Variant 7-37884321-T-C is Benign according to our data. Variant chr7-37884321-T-C is described in ClinVar as Benign. ClinVar VariationId is 164803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NME8	NM_016616.5 link	c.1013T>C	p.Ile338Thr	missense_variant	Exon 13 of 18	ENST00000199447.9	NP_057700.3	Q8N427

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NME8	ENST00000199447.9 link	c.1013T>C	p.Ile338Thr	missense_variant	Exon 13 of 18	1	NM_016616.5	ENSP00000199447.4	Q8N427
NME8	ENST00000440017.5 link	c.1013T>C	p.Ile338Thr	missense_variant	Exon 12 of 16	1		ENSP00000397063.1	Q8N427
ENSG00000290149	ENST00000476620.1 link	c.-38+26976T>C		intron_variant	Intron 2 of 3	4		ENSP00000425858.1	D6RIH7
NME8	ENST00000426106.1 link	n.124T>C		non_coding_transcript_exon_variant	Exon 3 of 5	5		ENSP00000408841.1	F8WEA2

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5478

AN:

152134

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0107

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0254

Gnomad ASJ

AF:

0.0649

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.0320

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0565

Gnomad OTH

AF:

0.0339

GnomAD2 exomes

AF:

0.0400

AC:

10028

AN:

250634

AF XY:

0.0415

show subpopulations

Gnomad AFR exome

AF:

0.00938

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0703

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0348

Gnomad NFE exome

AF:

0.0575

Gnomad OTH exome

AF:

0.0452

GnomAD4 exome

AF:

0.0508

AC:

72892

AN:

1435762

Hom.:

2077

Cov.:

AF XY:

0.0508

AC XY:

36343

AN XY:

716000

show subpopulations

African (AFR)

AF:

0.00764

AC:

252

AN:

32974

American (AMR)

AF:

0.0202

AC:

901

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0662

AC:

1717

AN:

25944

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39508

South Asian (SAS)

AF:

0.0319

AC:

2735

AN:

85786

European-Finnish (FIN)

AF:

0.0346

AC:

1849

AN:

53392

Middle Eastern (MID)

AF:

0.0696

AC:

395

AN:

5678

European-Non Finnish (NFE)

AF:

0.0572

AC:

62271

AN:

1088306

Other (OTH)

AF:

0.0466

AC:

2770

AN:

59496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

3019

6037

9056

12074

15093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2218

4436

6654

8872

11090

<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:

0.0359

AC:

5473

AN:

152252

Hom.:

135

Cov.:

AF XY:

0.0337

AC XY:

2506

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0107

AC:

444

AN:

41526

American (AMR)

AF:

0.0254

AC:

388

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0649

AC:

225

AN:

3466

East Asian (EAS)

AF:

0.000578

AC:

AN:

5194

South Asian (SAS)

AF:

0.0284

AC:

137

AN:

4818

European-Finnish (FIN)

AF:

0.0320

AC:

340

AN:

10612

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0565

AC:

3841

AN:

68024

Other (OTH)

AF:

0.0336

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

263

526

790

1053

1316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0500

Hom.:

452

Bravo

AF:

0.0333

TwinsUK

AF:

0.0558

AC:

207

ALSPAC

AF:

0.0623

AC:

240

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.0528

AC:

454

ExAC

AF:

0.0394

AC:

4783

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0558

EpiControl

AF:

0.0563

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ile338Thr in exon 13 of TXNDC3: This variant is not expected to have clinical si gnificance because it has been identified in 5.3% (454/8594) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs62001870). -

Primary ciliary dyskinesia

Benign:1

Sep 12, 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

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 6

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.73

.;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

3.3

M;M

PhyloP100

4.5

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.72

MPC

0.18

ClinPred

0.064

GERP RS

4.0

Varity_R

0.80

gMVP

0.76

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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