rs201867197
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016616.5(NME8):c.1341C>A(p.Phe447Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000868 in 1,613,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 0 hom. )
Consequence
NME8
NM_016616.5 missense
NM_016616.5 missense
Scores
3
7
8
Clinical Significance
Conservation
PhyloP100: 4.43
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NME8 | NM_016616.5 | c.1341C>A | p.Phe447Leu | missense_variant | 15/18 | ENST00000199447.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NME8 | ENST00000199447.9 | c.1341C>A | p.Phe447Leu | missense_variant | 15/18 | 1 | NM_016616.5 | P1 | |
NME8 | ENST00000440017.5 | c.1341C>A | p.Phe447Leu | missense_variant | 14/16 | 1 | P1 | ||
NME8 | ENST00000426106.1 | c.*287C>A | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250584Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135416
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GnomAD4 exome AF: 0.0000856 AC: 125AN: 1461134Hom.: 0 Cov.: 31 AF XY: 0.0000812 AC XY: 59AN XY: 726888
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GnomAD4 genome ? AF: 0.0000985 AC: 15AN: 152266Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74452
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 30, 2023 | ClinVar contains an entry for this variant (Variation ID: 578403). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NME8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with NME8-related conditions. This variant is present in population databases (rs201867197, gnomAD 0.01%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 447 of the NME8 protein (p.Phe447Leu). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Gain of disorder (P = 0.1563);Gain of disorder (P = 0.1563);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at