9-98081135-A-G

Variant names:

• chr9-98081135-A-G
• rs4237190
• NM_018946.4:c.870+53A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018946.4(NANS):​c.870+53A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 1,602,124 control chromosomes in the GnomAD database, including 225,964 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (30828 hom., cov: 32)
  • Exomes 𝑓: 0.51 (195136 hom.)
• Consequence: NANS NM_018946.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.326
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.85618).
• BP6: Variant 9-98081135-A-G is Benign according to our data. Variant chr9-98081135-A-G is described in ClinVar as Benign. ClinVar VariationId is 1278431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NANS	NM_018946.4	c.870+53A>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.870+53A>G		intron_variant	Intron 5 of 5	1	NM_018946.4	ENSP00000210444.5

Frequencies

GnomAD3 genomes AF: 0.608 AC: 92349 AN: 152000 Hom.: 30779 Cov.: 32

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.544 AC: 133303 AN: 244834 AF XY: 0.541

Gnomad AFR exome AF: 0.895

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.445

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.514

GnomAD4 exome AF: 0.511 AC: 740723 AN: 1450006 Hom.: 195136 Cov.: 35 AF XY: 0.513 AC XY: 369304 AN XY: 719212

African (AFR) AF: 0.904 AC: 30116 AN: 33332

American (AMR) AF: 0.662 AC: 29330 AN: 44298

Ashkenazi Jewish (ASJ) AF: 0.438 AC: 11298 AN: 25792

East Asian (EAS) AF: 0.339 AC: 13375 AN: 39446

South Asian (SAS) AF: 0.658 AC: 56242 AN: 85462

European-Finnish (FIN) AF: 0.385 AC: 20321 AN: 52764

Middle Eastern (MID) AF: 0.547 AC: 3126 AN: 5718

European-Non Finnish (NFE) AF: 0.495 AC: 546049 AN: 1103418

Other (OTH) AF: 0.516 AC: 30866 AN: 59776

GnomAD4 genome AF: 0.608 AC: 92458 AN: 152118 Hom.: 30828 Cov.: 32 AF XY: 0.602 AC XY: 44777 AN XY: 74364

African (AFR) AF: 0.885 AC: 36721 AN: 41508

American (AMR) AF: 0.634 AC: 9697 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1542 AN: 3470

East Asian (EAS) AF: 0.362 AC: 1874 AN: 5178

South Asian (SAS) AF: 0.667 AC: 3214 AN: 4816

European-Finnish (FIN) AF: 0.388 AC: 4107 AN: 10580

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.491 AC: 33392 AN: 67964

Other (OTH) AF: 0.591 AC: 1247 AN: 2110

Alfa AF: 0.534 Hom.: 41508

Bravo AF: 0.635

TwinsUK AF: 0.504 AC: 1869

ALSPAC AF: 0.501 AC: 1931

ExAC AF: 0.548 AC: 66576

Asia WGS AF: 0.564 AC: 1965 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.99
DANN	Benign	0.42
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.019	N
PhyloP100		-0.33
GERP RS		2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4237190; hg19: chr9-100843417; COSMIC: COSV52962982; COSMIC: COSV52962982;