rs10250905

chr7-37867702-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C208H) has been classified as Uncertain significance.

• 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

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]

ACMG classification

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	UniProt
NME8	NM_016616.5	c.622T>C	p.Cys208Arg	missense_variant, splice_region_variant	11/18	ENST00000199447.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NME8	ENST00000199447.9	c.622T>C	p.Cys208Arg	missense_variant, splice_region_variant	11/18	1	NM_016616.5	P1
NME8	ENST00000440017.5	c.622T>C	p.Cys208Arg	missense_variant, splice_region_variant	10/16	1		P1
NME8	ENST00000426106.1	c.105+10357T>C		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117148 AN: 151884 Hom.: 45487 Cov.: 31

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

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.: 32 AF XY: 0.737 AC XY: 533756 AN XY: 724446

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.: 31 AF XY: 0.768 AC XY: 57048 AN XY: 74308

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

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	Invitae	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	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.0030	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.010	N
MetaRNN	Benign	0.0000016	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.7e-15	P;P;P
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs10250905; hg19: chr7-37907304; COSMIC: COSV52253781; COSMIC: COSV52253781;