3-139578906-G-T
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001320510.2(NMNAT3):c.541C>A(p.Gln181Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
NMNAT3
NM_001320510.2 missense
NM_001320510.2 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 9.35
Genes affected
NMNAT3 (HGNC:20989): (nicotinamide nucleotide adenylyltransferase 3) This gene encodes a member of the nicotinamide/nicotinic acid mononucleotide adenylyltransferase family. These enzymes use ATP to catalyze the synthesis of nicotinamide adenine dinucleotide or nicotinic acid adenine dinucleotide from nicotinamide mononucleotide or nicotinic acid mononucleotide, respectively. The encoded protein is localized to mitochondria and may also play a neuroprotective role as a molecular chaperone. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.843
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NMNAT3 | NM_001401600.1 | c.259C>A | p.Gln87Lys | missense_variant | 5/7 | ENST00000704800.1 | NP_001388529.1 | |
NMNAT3 | NR_174944.1 | n.518C>A | non_coding_transcript_exon_variant | 3/4 | ||||
COPB2-DT | NR_121609.1 | n.413+1056G>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NMNAT3 | ENST00000704800.1 | c.259C>A | p.Gln87Lys | missense_variant | 5/7 | NM_001401600.1 | ENSP00000516041 | P2 | ||
COPB2-DT | ENST00000658348.1 | n.730+1056G>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251288Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135804
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GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727222
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GnomAD4 genome AF: 0.0000657 AC: 10AN: 152274Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74444
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2022 | The c.148C>A (p.Q50K) alteration is located in exon 3 (coding exon 1) of the NMNAT3 gene. This alteration results from a C to A substitution at nucleotide position 148, causing the glutamine (Q) at amino acid position 50 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;D;D;D;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;D;.;T;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;.;.;.;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;.;.;D;D;D;.;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;.;D;D;D;.;.;D
Sift4G
Uncertain
D;.;.;.;.;D;D;D;.;.;.
Polyphen
0.90
.;.;.;.;.;P;.;.;.;.;.
Vest4
MutPred
0.67
.;.;.;.;Gain of methylation at Q87 (P = 0.0158);Gain of methylation at Q87 (P = 0.0158);.;Gain of methylation at Q87 (P = 0.0158);.;Gain of methylation at Q87 (P = 0.0158);Gain of methylation at Q87 (P = 0.0158);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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