Variant rs386833994 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The ENST00000355773.6(SLC17A5):c.802_816del(p.Ser268_Asn272del) variant causes a 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. Variant has been reported in ClinVar as Pathogenic (★★). 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
ENST00000355773.6 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.05

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in ENST00000355773.6.

PP5

Variant 6-73635384-GATTTCTTAATGATGA-G is Pathogenic according to our data. Variant chr6-73635384-GATTTCTTAATGATGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 56558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-73635384-GATTTCTTAATGATGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC17A5	NM_012434.5 linkuse as main transcript	c.802_816del	p.Ser268_Asn272del	inframe_deletion	6/11	ENST00000355773.6	NP_036566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC17A5	ENST00000355773.6 linkuse as main transcript	c.802_816del	p.Ser268_Asn272del	inframe_deletion	6/11	1	NM_012434.5	ENSP00000348019	P1	Q9NRA2-1
SLC17A5	ENST00000481996.1 linkuse as main transcript	n.568_582del		non_coding_transcript_exon_variant	5/5	4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249338

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134848

show subpopulations

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 SAS 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.:

AF XY:

0.000105

AC XY:

AN XY:

683948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000318

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:

0.000132

Gnomad4 OTH exome

AF:

0.0000700

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Salla disease

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2024	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	This variant, c.802_816del, results in the deletion of 5 amino acid(s) of the SLC17A5 protein (p.Ser268_Asn272del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs386833994, gnomAD 0.006%). This variant has been observed in individual(s) with severe infantile sialic acid storage disease (PMID: 10581036, 12794688, 15805149). This variant is also known as 801-815del, SSLRN deletion, or "the ISSD deletion". ClinVar contains an entry for this variant (Variation ID: 56558). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC17A5 function (PMID: 12359136, 15510212). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 12, 2017	Variant summary: The SLC17A5 c.802_816del15 (p.Ser268_Asn272del) variant causes an in-frame deletion in the cytosolic loop between TM domains 6 and 7 (Aula_2000). This variant was found in 2/119968 control chromosomes at a frequency of 0.0000167, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC17A5 variant (0.0023717). Multiple publications cite the variant in affected homozygous and compound heterozygous individuals diagnosed with ISSD. 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) In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. -

Sialic acid storage disease, severe infantile type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2003

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 06, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 5 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15516337, 12121352, 15510212, 12359136, 21781115, 12794688, 10069709, 15805149, 10947946, 2334213, 16170568, 10581036) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over