rs74360232

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000355773.6(SLC17A5):​c.1324G>A​(p.Val442Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000691 in 1,613,950 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V442V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00054 ( 2 hom. )

Consequence

SLC17A5
ENST00000355773.6 missense

Scores

1
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 2.38
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.013000339).
BP6
Variant 6-73600377-C-T is Benign according to our data. Variant chr6-73600377-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235209.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=3, Uncertain_significance=1}. Variant chr6-73600377-C-T is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC17A5NM_012434.5 linkuse as main transcriptc.1324G>A p.Val442Ile missense_variant 10/11 ENST00000355773.6 NP_036566.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC17A5ENST00000355773.6 linkuse as main transcriptc.1324G>A p.Val442Ile missense_variant 10/111 NM_012434.5 ENSP00000348019 P1Q9NRA2-1

Frequencies

GnomAD3 genomes
AF:
0.00215
AC:
327
AN:
152096
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00589
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00769
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000353
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00113
AC:
283
AN:
251406
Hom.:
0
AF XY:
0.00101
AC XY:
137
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00609
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00685
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000264
Gnomad OTH exome
AF:
0.00114
GnomAD4 exome
AF:
0.000536
AC:
783
AN:
1461736
Hom.:
2
Cov.:
31
AF XY:
0.000484
AC XY:
352
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.00633
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00358
Gnomad4 SAS exome
AF:
0.000209
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000224
Gnomad4 OTH exome
AF:
0.00222
GnomAD4 genome
AF:
0.00218
AC:
332
AN:
152214
Hom.:
1
Cov.:
33
AF XY:
0.00215
AC XY:
160
AN XY:
74418
show subpopulations
Gnomad4 AFR
AF:
0.00602
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00751
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000353
Gnomad4 OTH
AF:
0.00331
Alfa
AF:
0.00100
Hom.:
0
Bravo
AF:
0.00239
ESP6500AA
AF:
0.00635
AC:
28
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00130
AC:
158
Asia WGS
AF:
0.00606
AC:
21
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:10
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023SLC17A5: BP4 -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 26, 2015- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Salla disease Benign:4
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria providedclinical testingNatera, Inc.Jan 11, 2020- -
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 28, 2015- -
Sialic acid storage disease, severe infantile type Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
SLC17A5-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 26, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
14
DANN
Benign
0.46
DEOGEN2
Benign
0.16
T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.45
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.0085
T
MetaRNN
Benign
0.013
T
MetaSVM
Benign
-0.97
T
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.010
N
REVEL
Benign
0.053
Sift
Benign
0.48
T
Sift4G
Benign
0.93
T
Polyphen
0.012
B
Vest4
0.24
MVP
0.43
MPC
0.15
ClinPred
0.0068
T
GERP RS
2.5
Varity_R
0.017
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

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

Other links and lift over

dbSNP: rs74360232; hg19: chr6-74310100; API