rs2281732

Variant names:

• chr9-98082725-A-G
• rs2281732
• NM_018946.4:c.871-121A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018946.4(NANS):​c.871-121A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 831,620 control chromosomes in the GnomAD database, including 30,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.31 (9346 hom., cov: 32)
  • Exomes 𝑓: 0.23 (21502 hom.)
• Consequence: NANS NM_018946.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.125

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 (BayesDel_noAF=-0.84).
• BP6: Variant 9-98082725-A-G is Benign according to our data. Variant chr9-98082725-A-G is described in ClinVar as [Benign]. Clinvar id is 1272811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NANS	NM_018946.4	c.871-121A>G		intron_variant	Intron 5 of 5	ENST00000210444.6	NP_061819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NANS	ENST00000210444.6	c.871-121A>G		intron_variant	Intron 5 of 5	1	NM_018946.4	ENSP00000210444.5
TRIM14	ENST00000375098.7	c.*28+4717T>C		intron_variant	Intron 6 of 6	2		ENSP00000364239.3
NANS	ENST00000461452.1	n.2798-121A>G		intron_variant	Intron 3 of 3	2
TRIM14	ENST00000478530.1	n.561-1464T>C		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46746 AN: 152008 Hom.: 9336 Cov.: 32

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.228 AC: 154624 AN: 679494 Hom.: 21502 AF XY: 0.237 AC XY: 83026 AN XY: 349724

Gnomad4 AFR exome AF: 0.574 AC: 9886 AN: 17228

Gnomad4 AMR exome AF: 0.227 AC: 5995 AN: 26430

Gnomad4 ASJ exome AF: 0.222 AC: 3636 AN: 16350

Gnomad4 EAS exome AF: 0.0927 AC: 2996 AN: 32316

Gnomad4 SAS exome AF: 0.494 AC: 26693 AN: 54060

Gnomad4 FIN exome AF: 0.191 AC: 7281 AN: 38102

Gnomad4 NFE exome AF: 0.194 AC: 88887 AN: 458848

Gnomad4 Remaining exome AF: 0.249 AC: 8369 AN: 33670

GnomAD4 genome AF: 0.308 AC: 46788 AN: 152126 Hom.: 9346 Cov.: 32 AF XY: 0.308 AC XY: 22895 AN XY: 74356

Gnomad4 AFR AF: 0.563 AC: 0.56329 AN: 0.56329

Gnomad4 AMR AF: 0.236 AC: 0.236498 AN: 0.236498

Gnomad4 ASJ AF: 0.232 AC: 0.231988 AN: 0.231988

Gnomad4 EAS AF: 0.127 AC: 0.127027 AN: 0.127027

Gnomad4 SAS AF: 0.500 AC: 0.499792 AN: 0.499792

Gnomad4 FIN AF: 0.201 AC: 0.200925 AN: 0.200925

Gnomad4 NFE AF: 0.191 AC: 0.191386 AN: 0.191386

Gnomad4 OTH AF: 0.286 AC: 0.286187 AN: 0.286187

Alfa AF: 0.246 Hom.: 2047

Bravo AF: 0.316

Asia WGS AF: 0.344 AC: 1199 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2281732; hg19: chr9-100845007;