rs386833994

Variant names:

• chr6-73635384-GATTTCTTAATGATGA-G
• rs386833994
• NM_012434.5:c.802_816delTCATCATTAAGAAAT

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM4 PP5_Very_Strong

The NM_012434.5(SLC17A5):​c.802_816delTCATCATTAAGAAAT​(p.Ser268_Asn272del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000095 in 1,516,276 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000699341: Functional studies found that due to this variant the ISSD polypeptide is mainly constrained to the Golgi compartment with limited presence in the lysosomes (Aula_2002) and also that it abrogates the transport activity of sialin (Wreden_2016)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S268S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SLC17A5 NM_012434.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.05
• Publications: 2 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000699341: Functional studies found that due to this variant the ISSD polypeptide is mainly constrained to the Golgi compartment with limited presence in the lysosomes (Aula_2002) and also that it abrogates the transport activity of sialin (Wreden_2016); SCV001198532: Experimental studies have shown that this variant affects SLC17A5 function (PMID: 12359136, 15510212).
• PM4: Nonframeshift variant in NON repetitive region in NM_012434.5.
• PP5: Variant 6-73635384-GATTTCTTAATGATGA-G is Pathogenic according to our data. Variant chr6-73635384-GATTTCTTAATGATGA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 56558.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.802_816delTCATCATTAAGAAAT	p.Ser268_Asn272del	conservative_inframe_deletion	Exon 6 of 11	NP_036566.1	Q9NRA2-1
	SLC17A5	NM_001382633.1		c.802_816delTCATCATTAAGAAAT	p.Ser268_Asn272del	conservative_inframe_deletion	Exon 6 of 12	NP_001369562.1
	SLC17A5	NM_001382631.1		c.823_837delTCATCATTAAGAAAT	p.Ser275_Asn279del	conservative_inframe_deletion	Exon 7 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.802_816delTCATCATTAAGAAAT	p.Ser268_Asn272del	conservative_inframe_deletion	Exon 6 of 11	ENSP00000348019.5	Q9NRA2-1
	SLC17A5	ENST00000957536.1		c.916_930delTCATCATTAAGAAAT	p.Ser306_Asn310del	conservative_inframe_deletion	Exon 7 of 12	ENSP00000627595.1
	SLC17A5	ENST00000957535.1		c.724_738delTCATCATTAAGAAAT	p.Ser242_Asn246del	conservative_inframe_deletion	Exon 6 of 11	ENSP00000627594.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000401 AC: 10 AN: 249338 AF XY: 0.0000519

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: 0.0000794

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000103 AC: 140 AN: 1364100 Hom.: 0 AF XY: 0.000105 AC XY: 72 AN XY: 683948

African (AFR) AF: 0.0000318 AC: 1 AN: 31472

American (AMR) AF: 0.00 AC: 0 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25490

East Asian (EAS) AF: 0.00 AC: 0 AN: 39050

South Asian (SAS) AF: 0.00 AC: 0 AN: 83692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5062

European-Non Finnish (NFE) AF: 0.000132 AC: 135 AN: 1025748

Other (OTH) AF: 0.0000700 AC: 4 AN: 57146

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Salla disease (7)
1	-	-	not provided (1)
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		7.0
Mutation Taster		=13/187	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386833994; hg19: chr6-74345107;