7-37894544-T-C

Position:

chr7-37894544-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016616.5(NME8):c.1478T>C(p.Ile493Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 1,607,030 control chromosomes in the GnomAD database, including 88,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I493I) has been classified as Benign.

Frequency

Genomes: 𝑓 0.25 ( 6054 hom., cov: 32)

Exomes 𝑓: 0.33 ( 82609 hom. )

Consequence

NME8
NM_016616.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0760

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032392144).

BP6

Variant 7-37894544-T-C is Benign according to our data. Variant chr7-37894544-T-C is described in ClinVar as [Benign]. Clinvar id is 178811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-37894544-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NME8	NM_016616.5 linkuse as main transcript	c.1478T>C	p.Ile493Thr	missense_variant	16/18	ENST00000199447.9	NP_057700.3	Q8N427

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NME8	ENST00000199447.9 linkuse as main transcript	c.1478T>C	p.Ile493Thr	missense_variant	16/18	1	NM_016616.5	ENSP00000199447.4	Q8N427
NME8	ENST00000440017.5 linkuse as main transcript	c.1478T>C	p.Ile493Thr	missense_variant	15/16	1		ENSP00000397063.1	Q8N427
ENSG00000290149	ENST00000476620.1 linkuse as main transcript	c.-38+37199T>C		intron_variant		4		ENSP00000425858.1	D6RIH7

Frequencies

GnomAD3 genomes

AF:

0.251

AC:

38051

AN:

151788

Hom.:

6053

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0677

Gnomad AMI

AF:

0.417

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.306

Gnomad EAS

AF:

0.137

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.323

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.361

Gnomad OTH

AF:

0.276

GnomAD3 exomes

AF:

0.273

AC:

68347

AN:

250580

Hom.:

10695

AF XY:

0.273

AC XY:

37012

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.0590

Gnomad AMR exome

AF:

0.237

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.128

Gnomad SAS exome

AF:

0.164

Gnomad FIN exome

AF:

0.327

Gnomad NFE exome

AF:

0.353

Gnomad OTH exome

AF:

0.305

GnomAD4 exome

AF:

0.328

AC:

476874

AN:

1455124

Hom.:

82609

Cov.:

AF XY:

0.324

AC XY:

234615

AN XY:

724196

show subpopulations

Gnomad4 AFR exome

AF:

0.0524

Gnomad4 AMR exome

AF:

0.243

Gnomad4 ASJ exome

AF:

0.300

Gnomad4 EAS exome

AF:

0.157

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.333

Gnomad4 NFE exome

AF:

0.360

Gnomad4 OTH exome

AF:

0.312

GnomAD4 genome

AF:

0.250

AC:

38041

AN:

151906

Hom.:

6054

Cov.:

AF XY:

0.246

AC XY:

18270

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0675

Gnomad4 AMR

AF:

0.247

Gnomad4 ASJ

AF:

0.306

Gnomad4 EAS

AF:

0.137

Gnomad4 SAS

AF:

0.162

Gnomad4 FIN

AF:

0.323

Gnomad4 NFE

AF:

0.361

Gnomad4 OTH

AF:

0.272

Alfa

AF:

0.338

Hom.:

13916

Bravo

AF:

0.240

TwinsUK

AF:

0.362

AC:

1341

ALSPAC

AF:

0.353

AC:

1360

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00896

AC:

ExAC

AF:

0.268

AC:

32518

Asia WGS

AF:

0.152

AC:

529

AN:

3472

EpiCase

AF:

0.350

EpiControl

AF:

0.343

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ile493Thr in exon 16 of TXNDC3: This variant is not expected to have clinical si gnificance because it has been identified in 28.7% (51/178) of English and Scott ish chromosomes from a broad population by the 1000 Genomes Project (http://www. ncbi.nlm.nih.gov/projects/SNP; dbSNP rs56128139). -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 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

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

6.8

DANN

Benign

0.59

DEOGEN2

Benign

0.019

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.28

.;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

0.50

N;N

REVEL

Benign

0.068

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.040

D;D

Polyphen

0.010

B;B

Vest4

0.30

MPC

0.025

ClinPred

0.0019

GERP RS

1.1

Varity_R

0.064

gMVP

0.29

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