NM_003042.4:c.305G>A

Variant names:

• chr3-11017909-G-A
• rs1553688027
• NM_003042.4:c.305G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003042.4(SLC6A1):​c.305G>A​(p.Cys102Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

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-AS1 (HGNC:40546): (SLC6A1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SLC6A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 67 curated pathogenic missense variants (we use a threshold of 10). The gene has 76 curated benign missense variants. Gene score misZ: 4.1766 (above the threshold of 3.09). Trascript score misZ: 4.9229 (above the threshold of 3.09). GenCC associations: The gene is linked to myoclonic-atonic epilepsy, myoclonic-astatic epilepsy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.305G>A	p.Cys102Tyr	missense_variant	Exon 4 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.305G>A	p.Cys102Tyr	missense_variant	Exon 4 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.020	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.013	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.
Vest4		0.79
MutPred		0.51		Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);Gain of catalytic residue at L97 (P = 0.0685);
MVP		0.48
MPC		2.5
ClinPred		0.94	D
GERP RS		4.1
Varity_R		0.41
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs1553688027; hg19: chr3-11059595;