NM_003042.4:c.1A>G

Variant names:

• chr3-11017212-A-G
• NM_003042.4:c.1A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_003042.4(SLC6A1):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.71

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 55 codons. Genomic position: 11017374. Lost 0.091 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-11017212-A-G is Pathogenic according to our data. Variant chr3-11017212-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3731558.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.1A>G	p.Met1?	start_lost	Exon 3 of 16	ENST00000287766.10	NP_003033.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A1	ENST00000287766.10	c.1A>G	p.Met1?	start_lost	Exon 3 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy with myoclonic atonic seizures Pathogenic:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SLC6A1 mRNA. The next in-frame methionine is located at codon 55. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC6A1-related conditions. This variant disrupts a region of the SLC6A1 protein in which other variant(s) (p.Arg44Trp) have been determined to be pathogenic (PMID: 30525188, 31785789, 34006619; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.;T;T;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.014	D
PROVEAN	Benign	-0.51	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0060	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.017	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.92	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;.;P;.;P;P;.;.;.
Vest4		0.92
MutPred		0.98		Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);Loss of MoRF binding (P = 0.1465);
MVP		0.95
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.46
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-11058898;