rs62001869

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 Benign. Variant got -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 id is 226853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-37884315-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
NME8	NM_016616.5 linkuse as main transcript	c.1007G>A	p.Arg336His	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>A	p.Arg336His	missense_variant	13/18	1	NM_016616.5	P1
NME8	ENST00000440017.5 linkuse as main transcript	c.1007G>A	p.Arg336His	missense_variant	12/16	1		P1
NME8	ENST00000426106.1 linkuse as main transcript	c.118G>A	p.Val40Ile	missense_variant, NMD_transcript_variant	3/5	5

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

GnomAD3 exomes

AF:

0.0143

AC:

3571

AN:

250530

Hom.:

AF XY:

0.0130

AC XY:

1762

AN XY:

135416

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 SAS exome

AF:

0.00170

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

Gnomad4 AFR exome

AF:

0.0514

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.0173

Gnomad4 EAS exome

AF:

0.000304

Gnomad4 SAS exome

AF:

0.00173

Gnomad4 FIN exome

AF:

0.0191

Gnomad4 NFE exome

AF:

0.0138

Gnomad4 OTH exome

AF:

0.0163

GnomAD4 genome

AF:

0.0248

AC:

3774

AN:

152062

Hom.:

Cov.:

AF XY:

0.0243

AC XY:

1804

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0520

Gnomad4 AMR

AF:

0.0159

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00395

Gnomad4 FIN

AF:

0.0182

Gnomad4 NFE

AF:

0.0154

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0146

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2014

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

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

DANN

Benign

0.87

DEOGEN2

Benign

0.0068

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00012

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

1.0

N;N;N

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

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

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