rs10250905

Positions:

chr7-37867702-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.622T>C(p.Cys208Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 1,607,556 control chromosomes in the GnomAD database, including 441,764 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 45537 hom., cov: 31)

Exomes 𝑓: 0.74 ( 396227 hom. )

Consequence

NME8
NM_016616.5 missense, splice_region

Scores

Splicing: ADA: 0.0003852

Clinical Significance

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

Conservation

PhyloP100: 1.17

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=1.56247E-6).

BP6

Variant 7-37867702-T-C is Benign according to our data. Variant chr7-37867702-T-C is described in ClinVar as [Benign]. Clinvar id is 164801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-37867702-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.865 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NME8	NM_016616.5 link	c.622T>C	p.Cys208Arg	missense_variant, splice_region_variant	11/18	ENST00000199447.9	NP_057700.3	Q8N427

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NME8	ENST00000199447.9 link	c.622T>C	p.Cys208Arg	missense_variant, splice_region_variant	11/18	1	NM_016616.5	ENSP00000199447.4	Q8N427
NME8	ENST00000440017.5 link	c.622T>C	p.Cys208Arg	missense_variant, splice_region_variant	10/16	1		ENSP00000397063.1	Q8N427
ENSG00000290149	ENST00000476620.1 link	c.-38+10357T>C		intron_variant		4		ENSP00000425858.1	D6RIH7
NME8	ENST00000426106.1 link	n.105+10357T>C		intron_variant		5		ENSP00000408841.1	F8WEA2

Frequencies

GnomAD3 genomes

AF:

0.771

AC:

117148

AN:

151884

Hom.:

45487

Cov.:

show subpopulations

Gnomad AFR

AF:

0.872

Gnomad AMI

AF:

0.818

Gnomad AMR

AF:

0.726

Gnomad ASJ

AF:

0.785

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.736

Gnomad FIN

AF:

0.713

Gnomad MID

AF:

0.753

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.776

GnomAD3 exomes

AF:

0.732

AC:

183376

AN:

250628

Hom.:

67672

AF XY:

0.733

AC XY:

99287

AN XY:

135504

show subpopulations

Gnomad AFR exome

AF:

0.871

Gnomad AMR exome

AF:

0.670

Gnomad ASJ exome

AF:

0.782

Gnomad EAS exome

AF:

0.562

Gnomad SAS exome

AF:

0.748

Gnomad FIN exome

AF:

0.727

Gnomad NFE exome

AF:

0.749

Gnomad OTH exome

AF:

0.744

GnomAD4 exome

AF:

0.736

AC:

1071706

AN:

1455554

Hom.:

396227

Cov.:

AF XY:

0.737

AC XY:

533756

AN XY:

724446

show subpopulations

Gnomad4 AFR exome

AF:

0.877

Gnomad4 AMR exome

AF:

0.679

Gnomad4 ASJ exome

AF:

0.784

Gnomad4 EAS exome

AF:

0.565

Gnomad4 SAS exome

AF:

0.748

Gnomad4 FIN exome

AF:

0.729

Gnomad4 NFE exome

AF:

0.738

Gnomad4 OTH exome

AF:

0.740

GnomAD4 genome

AF:

0.771

AC:

117255

AN:

152002

Hom.:

45537

Cov.:

AF XY:

0.768

AC XY:

57048

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.872

Gnomad4 AMR

AF:

0.726

Gnomad4 ASJ

AF:

0.785

Gnomad4 EAS

AF:

0.577

Gnomad4 SAS

AF:

0.737

Gnomad4 FIN

AF:

0.713

Gnomad4 NFE

AF:

0.745

Gnomad4 OTH

AF:

0.775

Alfa

AF:

0.755

Hom.:

56383

Bravo

AF:

0.775

TwinsUK

AF:

0.741

AC:

2748

ALSPAC

AF:

0.738

AC:

2844

ESP6500AA

AF:

0.864

AC:

3805

ESP6500EA

AF:

0.748

AC:

6432

ExAC

AF:

0.737

AC:

89500

Asia WGS

AF:

0.661

AC:

2300

AN:

3478

EpiCase

AF:

0.748

EpiControl

AF:

0.757

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	Jun 11, 2013	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 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

0.089

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0030

T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.061

.;T

MetaRNN

Benign

0.0000016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.070

Sift

Benign

0.046

D;D

Sift4G

Uncertain

0.029

D;D

Polyphen

0.0010

B;B

Vest4

0.13

MPC

0.026

ClinPred

0.010

GERP RS

4.9

Varity_R

0.32

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00039

dbscSNV1_RF

Benign

0.048

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