9-98076920-G-A

Position:

chr9-98076920-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000210444.6(NANS):c.351G>A(p.Met117Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,608,290 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 (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 7 hom. )

Consequence

NANS
ENST00000210444.6 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.55

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]

NANS links:

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]

TRIM14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 9-98076920-G-A is Benign according to our data. Variant chr9-98076920-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 734153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0013 (198/152202) while in subpopulation NFE AF= 0.00225 (153/68020). AF 95% confidence interval is 0.00196. There are 0 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NANS	NM_018946.4 linkuse as main transcript	c.351G>A	p.Met117Ile	missense_variant, splice_region_variant	3/6	ENST00000210444.6	NP_061819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NANS	ENST00000210444.6 linkuse as main transcript	c.351G>A	p.Met117Ile	missense_variant, splice_region_variant	3/6	1	NM_018946.4	ENSP00000210444	P1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00225

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00148

AC:

366

AN:

246678

Hom.:

AF XY:

0.00155

AC XY:

207

AN XY:

133312

show subpopulations

Gnomad AFR exome

AF:

0.000559

Gnomad AMR exome

AF:

0.000272

Gnomad ASJ exome

AF:

0.000400

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.000481

Gnomad FIN exome

AF:

0.00144

Gnomad NFE exome

AF:

0.00259

Gnomad OTH exome

AF:

0.000997

GnomAD4 exome

AF:

0.00238

AC:

3468

AN:

1456088

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

1628

AN XY:

724278

show subpopulations

Gnomad4 AFR exome

AF:

0.000422

Gnomad4 AMR exome

AF:

0.000228

Gnomad4 ASJ exome

AF:

0.000537

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.000625

Gnomad4 FIN exome

AF:

0.00156

Gnomad4 NFE exome

AF:

0.00288

Gnomad4 OTH exome

AF:

0.00151

GnomAD4 genome

AF:

0.00130

AC:

198

AN:

152202

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00225

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00208

Hom.:

Bravo

AF:

0.00114

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00156

AC:

190

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00175

EpiControl

AF:

0.00232

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NANS: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

NANS-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0014

Eigen

Benign

0.0070

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.017

MetaRNN

Benign

0.030

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.53

REVEL

Benign

0.27

Sift

Benign

0.28

Sift4G

Benign

0.20

Polyphen

0.0040

Vest4

0.76

MutPred

0.41

Gain of catalytic residue at M117 (P = 0.0075);

MVP

0.39

MPC

0.24

ClinPred

0.038

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.31

Position offset: 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over