rs119491110

Variant names:

• chr6-73615425-G-C
• rs119491110
• NM_012434.5:c.1001C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-73615425-G-C
• chr6-73615425-G-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_012434.5(SLC17A5):​c.1001C>G​(p.Pro334Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC17A5 NM_012434.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.80
• Publications: 16 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 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_012434.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 6-73615425-G-C is Pathogenic according to our data. Variant chr6-73615425-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5619.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.1001C>G	p.Pro334Arg	missense	Exon 8 of 11	NP_036566.1	Q9NRA2-1
	SLC17A5	NM_001382633.1		c.1001C>G	p.Pro334Arg	missense	Exon 8 of 12	NP_001369562.1
	SLC17A5	NM_001382631.1		c.1022C>G	p.Pro341Arg	missense	Exon 9 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.1001C>G	p.Pro334Arg	missense	Exon 8 of 11	ENSP00000348019.5	Q9NRA2-1
	SLC17A5	ENST00000957536.1		c.1115C>G	p.Pro372Arg	missense	Exon 9 of 12	ENSP00000627595.1
	SLC17A5	ENST00000957535.1		c.923C>G	p.Pro308Arg	missense	Exon 8 of 11	ENSP00000627594.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Sialic acid storage disease, severe infantile type (3)
1	-	-	Salla disease (1)
1	-	-	Sialic acid storage disease, severe infantile type;C1096903:Salla disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		8.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.88		Gain of methylation at P334 (P = 0.0823)
MVP		0.95
MPC		0.75
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.98
gMVP		0.98
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs119491110; hg19: chr6-74325148;