chr9-98056860-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018946.4(NANS):ā€‹c.52C>Gā€‹(p.Pro18Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,612,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 34)
Exomes š‘“: 0.000034 ( 0 hom. )

Consequence

NANS
NM_018946.4 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.17
Variant links:
Genes affected
NANS (HGNC:19237): (N-acetylneuraminate synthase) This gene encodes an enzyme that functions in the biosynthetic pathways of sialic acids. In vitro, the encoded protein uses N-acetylmannosamine 6-phosphate and mannose 6-phosphate as substrates to generate phosphorylated forms of N-acetylneuraminic acid (Neu5Ac) and 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (KDN), respectively; however, it exhibits much higher activity toward the Neu5Ac phosphate product. In insect cells, expression of this gene results in Neu5Ac and KDN production. This gene is related to the E. coli sialic acid synthase gene neuB, and it can partially restore sialic acid synthase activity in an E. coli neuB-negative mutant. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

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 Protein UniProt
NANSNM_018946.4 linkuse as main transcriptc.52C>G p.Pro18Ala missense_variant 1/6 ENST00000210444.6 NP_061819.2
TRIM14XM_047424162.1 linkuse as main transcriptc.*29-21047G>C intron_variant XP_047280118.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NANSENST00000210444.6 linkuse as main transcriptc.52C>G p.Pro18Ala missense_variant 1/61 NM_018946.4 ENSP00000210444 P1
NANSENST00000480925.1 linkuse as main transcriptn.91C>G non_coding_transcript_exon_variant 1/22
NANSENST00000495319.1 linkuse as main transcriptn.93C>G non_coding_transcript_exon_variant 1/53

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152238
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000773
AC:
19
AN:
245836
Hom.:
0
AF XY:
0.0000672
AC XY:
9
AN XY:
133868
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000908
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000197
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000363
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000336
AC:
49
AN:
1460024
Hom.:
0
Cov.:
38
AF XY:
0.0000289
AC XY:
21
AN XY:
726402
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000614
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152238
Hom.:
0
Cov.:
34
AF XY:
0.0000403
AC XY:
3
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000901
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000660
AC:
8
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 01, 2022This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 18 of the NANS protein (p.Pro18Ala). This variant is present in population databases (rs368286579, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with NANS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.064
T
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.068
T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.095
D
MetaRNN
Uncertain
0.56
D
MetaSVM
Benign
-0.61
T
MutationAssessor
Pathogenic
3.1
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-4.0
D
REVEL
Benign
0.28
Sift
Uncertain
0.013
D
Sift4G
Uncertain
0.010
D
Polyphen
1.0
D
Vest4
0.78
MVP
0.71
MPC
0.52
ClinPred
0.97
D
GERP RS
5.4
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.8
Varity_R
0.46
gMVP
0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368286579; hg19: chr9-100819142; API