6-73644452-C-T

Position:

• chr6-73644452-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012434.5(SLC17A5):​c.246G>A​(p.Ala82Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.082 in 1,613,430 control chromosomes in the GnomAD database, including 6,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1063 hom., cov: 33)
  • Exomes 𝑓: 0.079 (5427 hom.)
• Consequence: SLC17A5 NM_012434.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.753

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 6-73644452-C-T is Benign according to our data. Variant chr6-73644452-C-T is described in ClinVar as [Benign]. Clinvar id is 130316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-73644452-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.753 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC17A5	NM_012434.5	c.246G>A	p.Ala82Ala	synonymous_variant	2/11	ENST00000355773.6	NP_036566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC17A5	ENST00000355773.6	c.246G>A	p.Ala82Ala	synonymous_variant	2/11	1	NM_012434.5	ENSP00000348019.5
SLC17A5	ENST00000481996.1	n.12G>A		non_coding_transcript_exon_variant	1/5	4

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16303 AN: 152026 Hom.: 1062 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.0484

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.0730

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.0988 AC: 24837 AN: 251362 Hom.: 1433 AF XY: 0.0962 AC XY: 13074 AN XY: 135854

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.170

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.0488

Gnomad NFE exome AF: 0.0732

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.0793 AC: 115919 AN: 1461286 Hom.: 5427 Cov.: 32 AF XY: 0.0798 AC XY: 58003 AN XY: 727000

Gnomad4 AFR exome AF: 0.156

Gnomad4 AMR exome AF: 0.132

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.0504

Gnomad4 NFE exome AF: 0.0676

Gnomad4 OTH exome AF: 0.0981

GnomAD4 genome AF: 0.107 AC: 16324 AN: 152144 Hom.: 1063 Cov.: 33 AF XY: 0.107 AC XY: 7931 AN XY: 74384

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.0966

Gnomad4 FIN AF: 0.0484

Gnomad4 NFE AF: 0.0730

Gnomad4 OTH AF: 0.135

Alfa AF: 0.0856 Hom.: 1537

Bravo AF: 0.117

Asia WGS AF: 0.143 AC: 497 AN: 3478

EpiCase AF: 0.0832

EpiControl AF: 0.0836

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Salla disease Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sialic acid storage disease, severe infantile type Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2017	Variant summary: The SLC17A5 c.246G>A (p.Ala82Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 11883/121310 control chromosomes (671 homozygotes) at a frequency of 0.0979557, which is approximately 41 times the estimated maximal expected allele frequency of a pathogenic SLC17A5 variant (0.0023717), strong evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Due to the synonymous nature of the variant, the lack of predicted effect on splicing and the high frequency in the contol population, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.48

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: rs472294; hg19: chr6-74354175;