3-11017216-C-A

Variant names:

• chr3-11017216-C-A
• rs913073947
• NM_003042.4:c.5C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_003042.4(SLC6A1):​c.5C>A​(p.Ala2Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,252 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.52
• 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-AS1 (HGNC:40546): (SLC6A1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 3-11017216-C-A is Benign according to our data. Variant chr3-11017216-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1188750.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAdExome4 at 18 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A1	NM_003042.4	c.5C>A	p.Ala2Glu	missense_variant	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.5C>A	p.Ala2Glu	missense_variant	Exon 3 of 16	1	NM_003042.4	ENSP00000287766.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461252 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726846

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111652

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Sep 10, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

Epilepsy with myoclonic atonic seizures Benign:1

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.;T;T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.18	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;T;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.97	L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;.;L;L;.;.;.
PhyloP100		5.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.090	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0070	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.
Vest4		0.44
MutPred		0.24		Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);Loss of MoRF binding (P = 0.0308);
MVP		0.54
MPC		2.2
ClinPred		0.91	D
GERP RS		4.4
PromoterAI		-0.084	Neutral
Varity_R		0.19
gMVP		0.78
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs913073947; hg19: chr3-11058902;