9-98060802-T-C

Position:

• chr9-98060802-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018946.4(NANS):​c.153T>C​(p.Ala51Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,613,458 control chromosomes in the GnomAD database, including 231,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (30508 hom., cov: 33)
  • Exomes 𝑓: 0.52 (200518 hom.)
• Consequence: NANS NM_018946.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.117

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]

NANS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 9-98060802-T-C is Benign according to our data. Variant chr9-98060802-T-C is described in ClinVar as [Benign]. Clinvar id is 1250394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.117 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NANS	NM_018946.4	c.153T>C	p.Ala51Ala	synonymous_variant	2/6	ENST00000210444.6	NP_061819.2
TRIM14	XM_047424162.1	c.*29-24989A>G		intron_variant			XP_047280118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NANS	ENST00000210444.6	c.153T>C	p.Ala51Ala	synonymous_variant	2/6	1	NM_018946.4	ENSP00000210444.5
NANS	ENST00000480925.1	n.192T>C		non_coding_transcript_exon_variant	2/2	2
NANS	ENST00000495319.1	n.194T>C		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.606 AC: 92099 AN: 152012 Hom.: 30453 Cov.: 33

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.635

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.597

GnomAD3 exomes AF: 0.542 AC: 136386 AN: 251458 Hom.: 39435 AF XY: 0.539 AC XY: 73289 AN XY: 135898

Gnomad AFR exome AF: 0.881

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.322

Gnomad SAS exome AF: 0.668

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.496

Gnomad OTH exome AF: 0.518

GnomAD4 exome AF: 0.516 AC: 753969 AN: 1461328 Hom.: 200518 Cov.: 52 AF XY: 0.518 AC XY: 376842 AN XY: 727030

Gnomad4 AFR exome AF: 0.889

Gnomad4 AMR exome AF: 0.662

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.301

Gnomad4 SAS exome AF: 0.656

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.503

Gnomad4 OTH exome AF: 0.519

GnomAD4 genome AF: 0.606 AC: 92214 AN: 152130 Hom.: 30508 Cov.: 33 AF XY: 0.601 AC XY: 44653 AN XY: 74354

Gnomad4 AFR AF: 0.870

Gnomad4 AMR AF: 0.635

Gnomad4 ASJ AF: 0.445

Gnomad4 EAS AF: 0.324

Gnomad4 SAS AF: 0.664

Gnomad4 FIN AF: 0.398

Gnomad4 NFE AF: 0.497

Gnomad4 OTH AF: 0.595

Alfa AF: 0.530 Hom.: 28881

Bravo AF: 0.632

Asia WGS AF: 0.553 AC: 1926 AN: 3478

EpiCase AF: 0.491

EpiControl AF: 0.505

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Spondyloepimetaphyseal dysplasia, Genevieve type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs13049; hg19: chr9-100823084; COSMIC: COSV52965592;