rs794729653

Variant names:

• chr6-73641806-AT-A
• rs794729653
• NM_012434.5:c.409delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_012434.5(SLC17A5):​c.409delA​(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 NM_012434.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.29
• Publications: 4 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: G2P, Orphanet, Genomics England PanelApp, Myriad Women’s Health
• free sialic acid storage disease, infantile form

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 203395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC17A5	NM_012434.5	c.409delA	p.Met137CysfsTer3	frameshift_variant	Exon 3 of 11	ENST00000355773.6	NP_036566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC17A5	ENST00000355773.6	c.409delA	p.Met137CysfsTer3	frameshift_variant	Exon 3 of 11	1	NM_012434.5	ENSP00000348019.5
SLC17A5	ENST00000481996.1	n.175delA		non_coding_transcript_exon_variant	Exon 2 of 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 17, 2014

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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 . -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sialic acid storage disease, severe infantile type Pathogenic:1

Jul 17, 2014

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=7/193	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs794729653; hg19: chr6-74351529; COSMIC: COSV63288151;