NM_012434.5:c.1324G>A

Variant names:

• chr6-73600377-C-T
• rs74360232
• NM_012434.5:c.1324G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_012434.5(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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V442A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (2 hom.)
• Consequence: SLC17A5 NM_012434.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 2.38
• Publications: 6 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: G2P, Orphanet, Genomics England PanelApp, Myriad Women’s Health
• free sialic acid storage disease, infantile form

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• intermediate severe Salla disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 235209.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A5	NM_012434.5	MANE Select	c.1324G>A	p.Val442Ile	missense	Exon 10 of 11	NP_036566.1
	SLC17A5	NM_001382633.1		c.1324G>A	p.Val442Ile	missense	Exon 10 of 12	NP_001369562.1
	SLC17A5	NM_001382631.1		c.1345G>A	p.Val449Ile	missense	Exon 11 of 12	NP_001369560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC17A5	ENST00000355773.6	TSL:1 MANE Select	c.1324G>A	p.Val442Ile	missense	Exon 10 of 11	ENSP00000348019.5

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152096 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.00113 AC: 283 AN: 251406 AF XY: 0.00101

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 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

African (AFR) AF: 0.00633 AC: 212 AN: 33476

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00358 AC: 142 AN: 39696

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.000224 AC: 249 AN: 1111884

Other (OTH) AF: 0.00222 AC: 134 AN: 60390

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152214 Hom.: 1 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74418

African (AFR) AF: 0.00602 AC: 250 AN: 41540

American (AMR) AF: 0.000327 AC: 5 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00751 AC: 39 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00112 Hom.: 1

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	4	Salla disease (4)
-	-	1	not specified (1)
-	-	1	Sialic acid storage disease, severe infantile type (1)
-	-	1	SLC17A5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.4
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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs74360232; hg19: chr6-74310100;