9-98076925-T-C

Variant names:

• chr9-98076925-T-C
• rs200564294
• NM_018946.4:c.356T>C

Variant summary

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

The NM_018946.4(NANS):​c.356T>C​(p.Val119Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,878 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NANS NM_018946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.63

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

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 rank	MANE	Protein	UniProt
NANS	NM_018946.4	c.356T>C	p.Val119Ala	missense_variant	Exon 3 of 6	ENST00000210444.6	NP_061819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NANS	ENST00000210444.6	c.356T>C	p.Val119Ala	missense_variant	Exon 3 of 6	1	NM_018946.4	ENSP00000210444.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457878 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.015
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.28
Sift	Benign	0.35	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.89
MutPred		0.67		Gain of disorder (P = 0.0415);
MVP		0.56
MPC		0.27
ClinPred		0.86	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.73

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

Other links and lift over

dbSNP: rs200564294; hg19: chr9-100839207;