rs1234745577

Variant names:

• chr6-73595209-A-ATT
• rs1234745577
• NM_012434.5:c.1355_1356insAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_012434.5(SLC17A5):​c.1355_1356insAA​(p.Val453MetfsTer50) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002557689: "Clinically accredited laboratory assay specific to gene product shows abnormal protein function. This sample has been shown to have raised free sialic acid levels." (SP)".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SLC17A5 NM_012434.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 8.51
• Publications: 0 publications found

Genes affected

SLC17A5 (HGNC:10933): (solute carrier family 17 member 5) This gene encodes a membrane transporter that exports free sialic acids that have been cleaved off of cell surface lipids and proteins from lysosomes. Mutations in this gene cause sialic acid storage diseases, including infantile sialic acid storage disorder and and Salla disease, an adult form. [provided by RefSeq, Jul 2008]

SLC17A5 Gene-Disease associations (from GenCC):

• free sialic acid storage disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Salla disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, G2P, PanelApp Australia, Orphanet, Genomics England PanelApp
• free sialic acid storage disease, infantile form

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, Orphanet
• intermediate severe Salla disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0894 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002557689: "Clinically accredited laboratory assay specific to gene product shows abnormal protein function. This sample has been shown to have raised free sialic acid levels." (SP)
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-73595209-A-ATT is Pathogenic according to our data. Variant chr6-73595209-A-ATT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 558174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012434.5. 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
	SLC17A5	NM_012434.5	MANE Select	c.1355_1356insAA	p.Val453MetfsTer50	frameshift	Exon 11 of 11	NP_036566.1	Q9NRA2-1
	SLC17A5	NM_001382633.1		c.1453_1454insAA	p.Leu485GlnfsTer16	frameshift	Exon 12 of 12	NP_001369562.1
	SLC17A5	NM_001382631.1		c.1376_1377insAA	p.Val460MetfsTer50	frameshift	Exon 12 of 12	NP_001369560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A5	ENST00000355773.6	TSL:1 MANE Select	c.1355_1356insAA	p.Val453MetfsTer50	frameshift	Exon 11 of 11	ENSP00000348019.5	Q9NRA2-1
	SLC17A5	ENST00000957536.1		c.1469_1470insAA	p.Val491MetfsTer50	frameshift	Exon 12 of 12	ENSP00000627595.1
	SLC17A5	ENST00000957535.1		c.1277_1278insAA	p.Val427MetfsTer50	frameshift	Exon 11 of 11	ENSP00000627594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250158 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	1	-	Salla disease (6)
1	-	-	Sialic acid storage disease, severe infantile type (1)
1	-	-	Sialic acid storage disease, severe infantile type;C1096903:Salla disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.5
Mutation Taster		=20/180	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1234745577; hg19: chr6-74304932;