5-36671106-A-G

Variant names:

• chr5-36671106-A-G
• rs752276609
• NM_004172.5:c.397A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004172.5(SLC1A3):​c.397A>G​(p.Ile133Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,612,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I133T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SLC1A3 NM_004172.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.20
• Publications: 2 publications found

Genes affected

SLC1A3 (HGNC:10941): (solute carrier family 1 member 3) This gene encodes a member of a member of a high affinity glutamate transporter family. This gene functions in the termination of excitatory neurotransmission in central nervous system. Mutations are associated with episodic ataxia, Type 6. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2014]

SLC1A3-AS1 (HGNC:56374): (SLC1A3 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21065965).
• BS2: High AC in GnomAdExome4 at 26 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004172.5. 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
	SLC1A3	NM_004172.5	MANE Select	c.397A>G	p.Ile133Val	missense	Exon 4 of 10	NP_004163.3
	SLC1A3	NM_001438458.1		c.397A>G	p.Ile133Val	missense	Exon 4 of 11	NP_001425387.1
	SLC1A3	NM_001438454.1		c.397A>G	p.Ile133Val	missense	Exon 5 of 11	NP_001425383.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC1A3	ENST00000265113.9	TSL:1 MANE Select	c.397A>G	p.Ile133Val	missense	Exon 4 of 10	ENSP00000265113.4	P43003-1
	SLC1A3	ENST00000381918.4	TSL:1	c.397A>G	p.Ile133Val	missense	Exon 4 of 10	ENSP00000371343.4	P43003-1
	SLC1A3	ENST00000680232.1		c.397A>G	p.Ile133Val	missense	Exon 4 of 11	ENSP00000506207.1	A0A7P0TAG7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251140 AF XY: 0.0000442

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460424 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726654

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1110692

Other (OTH) AF: 0.0000166 AC: 1 AN: 60356

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Episodic ataxia type 6 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Benign	0.16	T
Polyphen		0.0060	B
Vest4		0.38
MutPred		0.53		Gain of catalytic residue at I133 (P = 0.0084)
MVP		0.52
MPC		0.37
ClinPred		0.070	T
GERP RS		3.5
Varity_R		0.094
gMVP		0.84
Mutation Taster		=46/54	disease causing

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: rs752276609; hg19: chr5-36671208; COSMIC: COSV54314281; COSMIC: COSV54314281;