9-98056809-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018946.4(NANS):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000144 in 1,592,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NANS NM_018946.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.70

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:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-98056809-A-G is Pathogenic according to our data. Variant chr9-98056809-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810396.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NANS	NM_018946.4	c.1A>G	p.Met1?	start_lost	1/6	ENST00000210444.6
TRIM14	XM_047424162.1	c.*29-20996T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NANS	ENST00000210444.6	c.1A>G	p.Met1?	start_lost	1/6	1	NM_018946.4	P1
NANS	ENST00000480925.1	n.40A>G		non_coding_transcript_exon_variant	1/2	2
NANS	ENST00000495319.1	n.42A>G		non_coding_transcript_exon_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151634 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 243952 Hom.: 0 AF XY: 0.0000300 AC XY: 4 AN XY: 133258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000153 AC: 22 AN: 1440680 Hom.: 0 Cov.: 41 AF XY: 0.0000167 AC XY: 12 AN XY: 717044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000520

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000910

Gnomad4 OTH exome AF: 0.0000511

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151634 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74070

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2019

- -

Spondyloepimetaphyseal dysplasia, Genevieve type Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Apr 25, 2022

The homozygous start-loss variant c.1A>G (p.1M?) has an allele frequency-0.0018% in gnomAD (aggregated) database and 0.0033% in 1000g databases. In-silico bioinformatic software predicts this variant by mutation taster as Disease causing. Phenotype observed were micromelia, bilateral hydrocephalus, cerebellar hypoplasia, hypoplastic nasal bone and hydrops. Spondyloepimetaphyseal dysplasia, Camera-Genevieve type is an autosomal recessive disorder. This is also known as NANS-CDG as sialic acid plays a vital role in multiple cellular functions. We classify this variant as likely pathogenic based on the phenotypes. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0037	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.021	D
Polyphen		0.83	P
Vest4		0.91
MutPred		0.97		Loss of loop (P = 0.0804);
MVP		0.60
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.82
gMVP		0.78

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: rs369033671; hg19: chr9-100819091;