rs139706489

Variant names:

• chr9-98056861-C-G
• rs139706489
• NM_018946.4:c.53C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-98056861-C-G
• chr9-98056861-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018946.4(NANS):​c.53C>G​(p.Pro18Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P18A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 34)
• Consequence: NANS NM_018946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.13
• Publications: 6 publications found

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]

TRIM14 (HGNC:16283): (tripartite motif containing 14) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic bodies and its function has not been determined. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NANS	NM_018946.4	MANE Select	c.53C>G	p.Pro18Arg	missense	Exon 1 of 6	NP_061819.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NANS	ENST00000210444.6	TSL:1 MANE Select	c.53C>G	p.Pro18Arg	missense	Exon 1 of 6	ENSP00000210444.5	Q9NR45
	NANS	ENST00000924305.1		c.53C>G	p.Pro18Arg	missense	Exon 1 of 7	ENSP00000594364.1
	NANS	ENST00000924304.1		c.53C>G	p.Pro18Arg	missense	Exon 1 of 6	ENSP00000594363.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 39

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152240 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74370

African (AFR) AF: 0.0000482 AC: 2 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.32
Sift	Benign	0.11	T
Sift4G	Benign	0.12	T
Polyphen		0.97	D
Vest4		0.89
MutPred		0.59		Gain of solvent accessibility (P = 0.0584)
MVP		0.79
MPC		0.28
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		-0.049	Neutral
Varity_R		0.63
gMVP		0.76
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs139706489; hg19: chr9-100819143;