Genetic Variant NM_177550.5:c.1643G>A (chr17-6686271-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_177550.5(SLC13A5):c.1643G>A(p.Gly548Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,876 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC13A5
NM_177550.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.76

Publications

0 publications found

Variant links:

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 links:

ENSG00000290366 (HGNC:):

ENSG00000290366 links:

C17orf100 (HGNC:34494): (chromosome 17 open reading frame 100)

C17orf100 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC13A5	NM_177550.5	MANE Select	c.1643G>A	p.Gly548Glu	missense	Exon 12 of 12	NP_808218.1	Q86YT5-1
SLC13A5	NM_001284509.2		c.1592G>A	p.Gly531Glu	missense	Exon 12 of 12	NP_001271438.1	Q86YT5-3
SLC13A5	NM_001284510.2		c.1514G>A	p.Gly505Glu	missense	Exon 11 of 11	NP_001271439.1	Q86YT5-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC13A5	ENST00000433363.7	TSL:1 MANE Select	c.1643G>A	p.Gly548Glu	missense	Exon 12 of 12	ENSP00000406220.2	Q86YT5-1
SLC13A5	ENST00000573648.5	TSL:1	c.1505G>A	p.Gly502Glu	missense	Exon 11 of 11	ENSP00000459372.1	Q86YT5-2
SLC13A5	ENST00000898130.1		c.1631G>A	p.Gly544Glu	missense	Exon 12 of 12	ENSP00000568189.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 25 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.078

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.97

MutationAssessor

Pathogenic

3.9

PhyloP100

4.8

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.54

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0040

Polyphen

0.24

Vest4

0.83

MutPred

0.85

Loss of methylation at R549 (P = 0.0402)

MVP

0.42

MPC

0.77

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.98

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over