dbSNP rs56128139: NME8:p.Ile493Lys (chr7-37894544-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016616.5(NME8):c.1478T>A(p.Ile493Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I493T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NME8
NM_016616.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0760

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
primary ciliary dyskinesia 6
Inheritance: AR Classification: LIMITED Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

NME8 links:

ENSG00000290149 (HGNC:):

ENSG00000290149 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NME8	NM_016616.5 link	c.1478T>A	p.Ile493Lys	missense_variant	Exon 16 of 18	ENST00000199447.9	NP_057700.3	Q8N427

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NME8	ENST00000199447.9 link	c.1478T>A	p.Ile493Lys	missense_variant	Exon 16 of 18	1	NM_016616.5	ENSP00000199447.4	Q8N427
NME8	ENST00000440017.5 link	c.1478T>A	p.Ile493Lys	missense_variant	Exon 15 of 16	1		ENSP00000397063.1	Q8N427
ENSG00000290149	ENST00000476620.1 link	c.-38+37199T>A		intron_variant	Intron 2 of 3	4		ENSP00000425858.1	D6RIH7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725426

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108522

Other (OTH)

AF:

0.00

AC:

AN:

60222

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

17722

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

8.7

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.043

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.35

.;T

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N

PhyloP100

0.076

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.050

B;B

Vest4

0.59

MutPred

0.63

Gain of disorder (P = 0.0032);Gain of disorder (P = 0.0032);

MVP

0.20

MPC

0.033

ClinPred

0.12

GERP RS

1.1

Varity_R

0.17

gMVP

0.58

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over