chr17-6695784-G-A

Variant names:

• chr17-6695784-G-A
• rs773770609
• NM_177550.5:c.997C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_177550.5(SLC13A5):​c.997C>T​(p.Arg333*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SLC13A5 NM_177550.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.85
• Publications: 6 publications found

Genes affected

SLC13A5 (HGNC:23089): (solute carrier family 13 member 5) This gene encodes a protein belonging to the solute carrier family 13 group of proteins. This family member is a sodium-dependent citrate cotransporter that may regulate metabolic processes. Mutations in this gene cause early infantile epileptic encephalopathy 25. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

SLC13A5 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 25

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• amelocerebrohypohidrotic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyridoxine-dependent epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-6695784-G-A is Pathogenic according to our data. Variant chr17-6695784-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177550.5. 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
	SLC13A5	NM_177550.5	MANE Select	c.997C>T	p.Arg333*	stop_gained	Exon 7 of 12	NP_808218.1
	SLC13A5	NM_001284509.2		c.946C>T	p.Arg316*	stop_gained	Exon 7 of 12	NP_001271438.1
	SLC13A5	NM_001284510.2		c.868C>T	p.Arg290*	stop_gained	Exon 6 of 11	NP_001271439.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC13A5	ENST00000433363.7	TSL:1 MANE Select	c.997C>T	p.Arg333*	stop_gained	Exon 7 of 12	ENSP00000406220.2
	SLC13A5	ENST00000573648.5	TSL:1	c.997C>T	p.Arg333*	stop_gained	Exon 7 of 11	ENSP00000459372.1
	SLC13A5	ENST00000293800.10	TSL:2	c.946C>T	p.Arg316*	stop_gained	Exon 7 of 12	ENSP00000293800.6

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251334 AF XY: 0.0000294

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000404 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Developmental and epileptic encephalopathy, 25 (8)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		2.8
Vest4		0.93
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	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: rs773770609; hg19: chr17-6599103;