rs1064795099

chr3-11031230-C-Achr3-11031230-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_Very_Strong PM1 PM2 PP2 PP3_Moderate PP5

The NM_003042.4(SLC6A1):c.1377C>A(p.Ser459Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S459T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC6A1 NM_003042.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_003042.4 (SLC6A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 570384
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_003042.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SLC6A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 3-11031230-C-A is Pathogenic according to our data. Variant chr3-11031230-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421382.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A1	NM_003042.4	c.1377C>A	p.Ser459Arg	missense_variant	13/16	ENST00000287766.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A1	ENST00000287766.10	c.1377C>A	p.Ser459Arg	missense_variant	13/16	1	NM_003042.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2019	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 that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32277047) -

Marfanoid habitus and intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.92	D;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	0.28	D
MutationAssessor	Pathogenic	3.5	H;H;H;H;H;.;H;.;H;H;H;H;.;H;H;H;.;H;H;H;.;H;H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
Polyphen		0.99	D;D;D;D;D;.;D;.;D;D;D;D;.;D;D;D;.;D;D;D;.;D;D;D;.
Vest4		0.85
MutPred		0.84		Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);Gain of methylation at S459 (P = 0.0352);.;
MVP		0.95
MPC		1.8
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.98

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: rs1064795099; hg19: chr3-11072916;