NM_018946.4:c.53C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018946.4(NANS):​c.53C>T​(p.Pro18Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0018 in 1,612,304 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). 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 0.0016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: NANS NM_018946.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032981426).
• BP6: Variant 9-98056861-C-T is Benign according to our data. Variant chr9-98056861-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 728546.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00163 (248/152354) while in subpopulation NFE AF = 0.00243 (165/68022). AF 95% confidence interval is 0.00212. There are 0 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

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>T	p.Pro18Leu	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>T	p.Pro18Leu	missense	Exon 1 of 6	ENSP00000210444.5	Q9NR45
	NANS	ENST00000924305.1		c.53C>T	p.Pro18Leu	missense	Exon 1 of 7	ENSP00000594364.1
	NANS	ENST00000924304.1		c.53C>T	p.Pro18Leu	missense	Exon 1 of 6	ENSP00000594363.1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00198 AC: 487 AN: 245624 AF XY: 0.00202

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.00313

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00182 AC: 2660 AN: 1459950 Hom.: 7 Cov.: 39 AF XY: 0.00170 AC XY: 1237 AN XY: 726366

African (AFR) AF: 0.0000601 AC: 2 AN: 33274

American (AMR) AF: 0.000246 AC: 11 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86160

European-Finnish (FIN) AF: 0.00552 AC: 291 AN: 52752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00202 AC: 2242 AN: 1111408

Other (OTH) AF: 0.00184 AC: 111 AN: 60272

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152354 Hom.: 0 Cov.: 34 AF XY: 0.00175 AC XY: 130 AN XY: 74494

African (AFR) AF: 0.000289 AC: 12 AN: 41594

American (AMR) AF: 0.000588 AC: 9 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00243 AC: 165 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00167 Hom.: 1

Bravo AF: 0.00130

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00268 AC: 23

ExAC AF: 0.00247 AC: 299

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	NANS-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.89
MPC		0.61
ClinPred		0.21	T
GERP RS		5.4
PromoterAI		-0.23	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.69
gMVP		0.79
Mutation Taster		=77/23	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;