rs146777129

Positions:

chr7-37865606-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_016616.5(NME8):c.610A>G(p.Ile204Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,608,044 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 2 hom. )

Consequence

NME8
NM_016616.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 1.28

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:

ENSG00000290149 (HGNC:):

ENSG00000290149 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013070345).

BP6

Variant 7-37865606-A-G is Benign according to our data. Variant chr7-37865606-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241113.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NME8	NM_016616.5 linkuse as main transcript	c.610A>G	p.Ile204Val	missense_variant	10/18	ENST00000199447.9	NP_057700.3	Q8N427

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NME8	ENST00000199447.9 linkuse as main transcript	c.610A>G	p.Ile204Val	missense_variant	10/18	1	NM_016616.5	ENSP00000199447.4		Q8N427
ENSG00000290149	ENST00000476620.1 linkuse as main transcript	c.-38+8261A>G		intron_variant		4		ENSP00000425858.1		D6RIH7

Frequencies

GnomAD3 genomes

AF:

0.000887

AC:

135

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00104

AC:

261

AN:

250818

Hom.:

AF XY:

0.00100

AC XY:

136

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00214

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.00170

AC:

2478

AN:

1455794

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1183

AN XY:

724716

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.00214

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.000887

AC:

135

AN:

152250

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00128

AC:

156

EpiCase

AF:

0.00164

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 6

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 13, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	The NME8 c.610A>G; p.Ile204Val variant (rs146777129), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 241113). This variant is found in the general population with an overall allele frequency of 0.10% (294/128722 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.018). Due to limited information, the clinical significance of this variant is uncertain at this time. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 19, 2016

- -

Primary ciliary dyskinesia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2019

This alteration is classified as likely 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. -

NME8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

3.9

DANN

Benign

0.59

DEOGEN2

Benign

0.0081

T;.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.37

.;T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;.;L

PrimateAI

Benign

0.35

PROVEAN

Benign

0.040

N;N;N

REVEL

Benign

0.018

Sift

Benign

0.088

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.030

B;.;B

Vest4

0.14

MVP

0.35

MPC

0.022

ClinPred

0.011

GERP RS

1.4

Varity_R

0.063

gMVP

0.12

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

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