rs1553692346

Variant names:

• chr3-11036890-A-T
• rs1553692346
• NM_003042.4:c.1724A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_003042.4(SLC6A1):​c.1724A>T​(p.Glu575Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E575K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.88
• Publications: 0 publications found

Genes affected

SLC6A1 (HGNC:11042): (solute carrier family 6 member 1) The protein encoded by this gene is a gamma-aminobutyric acid (GABA) transporter that localizes to the plasma membrane. The encoded protein removes GABA from the synaptic cleft, restoring it to presynaptic terminals. [provided by RefSeq, Jan 2017]

SLC6A1 Gene-Disease associations (from GenCC):

• epilepsy with myoclonic atonic seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16347033).
• BP6: Variant 3-11036890-A-T is Benign according to our data. Variant chr3-11036890-A-T is described in ClinVar as Benign. ClinVar VariationId is 542199.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003042.4. 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
	SLC6A1	NM_003042.4	MANE Select	c.1724A>T	p.Glu575Val	missense	Exon 16 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.1724A>T	p.Glu575Val	missense	Exon 16 of 16	NP_001335179.1
	SLC6A1	NM_001348251.2		c.1364A>T	p.Glu455Val	missense	Exon 16 of 16	NP_001335180.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A1	ENST00000287766.10	TSL:1 MANE Select	c.1724A>T	p.Glu575Val	missense	Exon 16 of 16	ENSP00000287766.4
	SLC6A1	ENST00000698198.1		c.1796A>T	p.Glu599Val	missense	Exon 14 of 14	ENSP00000513602.1
	SLC6A1	ENST00000644803.1		c.1751A>T	p.Glu584Val	missense	Exon 14 of 14	ENSP00000494469.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy with myoclonic atonic seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.0048	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Benign	0.16	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.39		Loss of disorder (P = 0.0082)
MVP		0.70
MPC		1.2
ClinPred		0.55	D
GERP RS		4.4
Varity_R		0.16
gMVP		0.57
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1553692346; hg19: chr3-11078576;