rs794729653

Positions:

• chr6-73641806-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000355773.6(SLC17A5):​c.409del​(p.Met137CysfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC17A5 ENST00000355773.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-73641806-AT-A is Pathogenic according to our data. Variant chr6-73641806-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC17A5	NM_012434.5	c.409del	p.Met137CysfsTer3	frameshift_variant	3/11	ENST00000355773.6	NP_036566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC17A5	ENST00000355773.6	c.409del	p.Met137CysfsTer3	frameshift_variant	3/11	1	NM_012434.5	ENSP00000348019	P1
SLC17A5	ENST00000481996.1	n.175del		non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Salla disease Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 08, 2022	This sequence change creates a premature translational stop signal (p.Met137Cysfs*3) in the SLC17A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC17A5 are known to be pathogenic (PMID: 10581036, 10947946, 15172001). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC17A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 203395). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 30, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 17, 2014	The SLC17A5 gene variant (c.409delA; p.Met137Cysfs*3) identified in this patient is a novel frameshift variant, which results in a truncated protein, considered a pathogenic variant . -

Sialic acid storage disease, severe infantile type Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Jul 17, 2014

The SLC17A5 gene variant (c.409delA; p.Met137Cysfs*3) identified in this patient is a novel frameshift variant, which results in a truncated protein, considered a pathogenic variant . -

Computational scores

Source: dbNSFP v4.3

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: rs794729653; hg19: chr6-74351529;