rs879255602

Variant names:

• chr9-98078183-GATTAC-ATGG
• rs879255602
• NM_018946.4:c.449-10_449-5delGATTACinsATGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP5_Moderate

The NM_018946.4(NANS):​c.449-10_449-5delGATTACinsATGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004679445: Studies have shown that this variant results in skipping of exons 3 and 4, but is expected to preserve the integrity of the reading-frame (PMID:27213289).".

• Frequency: Genomes: not found (cov: 31)
• Consequence: NANS NM_018946.4 splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.806
• Publications: 0 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004679445: Studies have shown that this variant results in skipping of exons 3 and 4, but is expected to preserve the integrity of the reading-frame (PMID: 27213289).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-98078183-GATTAC-ATGG is Pathogenic according to our data. Variant chr9-98078183-GATTAC-ATGG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 235184.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018946.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NANS	NM_018946.4	MANE Select	c.449-10_449-5delGATTACinsATGG		splice_region intron	N/A	NP_061819.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NANS	ENST00000210444.6	TSL:1 MANE Select	c.449-10_449-5delGATTACinsATGG		splice_region intron	N/A	ENSP00000210444.5	Q9NR45
	NANS	ENST00000415280.1	TSL:5	c.16_21delGATTACinsATGG	p.Asp6MetfsTer46	frameshift missense	Exon 2 of 3	ENSP00000404107.1	Q5TBR1
	TRIM14	ENST00000869645.1		c.*227_*232delGTAATCinsCCAT		3_prime_UTR	Exon 7 of 7	ENSP00000539704.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Spondyloepimetaphyseal dysplasia, Genevieve type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81
Mutation Taster		=5/95	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs879255602; hg19: chr9-100840465;