9-98056906-T-C

Variant names:

• chr9-98056906-T-C
• rs1017453701
• NM_018946.4:c.98T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS1

The NM_018946.4(NANS):​c.98T>C​(p.Leu33Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,118 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. L33R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NANS NM_018946.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.31
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000617 (9/1458118) while in subpopulation MID AF = 0.000525 (3/5712). AF 95% confidence interval is 0.000142. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.

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.98T>C	p.Leu33Pro	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.98T>C	p.Leu33Pro	missense	Exon 1 of 6	ENSP00000210444.5	Q9NR45
	NANS	ENST00000924305.1		c.98T>C	p.Leu33Pro	missense	Exon 1 of 7	ENSP00000594364.1
	NANS	ENST00000924304.1		c.98T>C	p.Leu33Pro	missense	Exon 1 of 6	ENSP00000594363.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458118 Hom.: 0 Cov.: 38 AF XY: 0.00000689 AC XY: 5 AN XY: 725436

African (AFR) AF: 0.00 AC: 0 AN: 32862

American (AMR) AF: 0.00 AC: 0 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39384

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52742

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110572

Other (OTH) AF: 0.0000166 AC: 1 AN: 60216

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.45
Sift	Benign	0.12	T
Sift4G	Benign	0.10	T
Polyphen		0.015	B
Vest4		0.78
MutPred		0.77		Gain of disorder (P = 0.0115)
MVP		0.67
MPC		0.35
ClinPred		0.97	D
GERP RS		5.4
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.95
gMVP		0.90
Mutation Taster		=17/83	disease causing

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: rs1017453701; hg19: chr9-100819188;