chr3-11017909-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C102F) has been classified as Uncertain significance.

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

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_003042.4
• PM2: Very rare variant in population databases, with high coverage

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.305G>A	p.Cys102Tyr	missense	Exon 4 of 16	NP_003033.3
	SLC6A1	NM_001348250.2		c.305G>A	p.Cys102Tyr	missense	Exon 4 of 16	NP_001335179.1
	SLC6A1	NM_001348251.2		c.-56G>A		5_prime_UTR	Exon 4 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.305G>A	p.Cys102Tyr	missense	Exon 4 of 16	ENSP00000287766.4
	SLC6A1	ENST00000698198.1		c.377G>A	p.Cys126Tyr	missense	Exon 2 of 14	ENSP00000513602.1
	SLC6A1	ENST00000644803.1		c.305G>A	p.Cys102Tyr	missense	Exon 2 of 14	ENSP00000494469.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
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
Vest4		0.79
MutPred		0.51		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
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs1553688027; hg19: chr3-11059595;