1-110167098-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_001010898.4(SLC6A17):c.169G>A(p.Ala57Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,610,442 control chromosomes in the GnomAD database, including 153,741 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (10392 hom., cov: 25)
  • Exomes 𝑓: 0.43 (143349 hom.)
• Consequence: SLC6A17 NM_001010898.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.681

Genes affected

SLC6A17 (HGNC:31399): (solute carrier family 6 member 17) The protein encoded by this gene is a member of the SLC6 family of transporters, which are responsible for the presynaptic uptake of most neurotransmitters. The encoded vesicular transporter is selective for proline, glycine, leucine and alanine. In mouse, the strongest expression of this gene was in cortical and hippocampal tissues where expression increased during embryonic brain development and peaked postnatally. Defects in this gene cause a form of autosomal recessive intellectual disability. [provided by RefSeq, Jul 2017]

SLC6A17-AS1 (HGNC:41279): (SLC6A17 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC6A17
• BP4: Computational evidence support a benign effect (MetaRNN=6.933941E-5).
• BP6: Variant 1-110167098-G-A is Benign according to our data. Variant chr1-110167098-G-A is described in ClinVar as [Benign]. Clinvar id is 1333112.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-110167098-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A17	NM_001010898.4	c.169G>A	p.Ala57Thr	missense_variant	2/12	ENST00000331565.5
SLC6A17-AS1	NR_183667.1	n.521C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A17	ENST00000331565.5	c.169G>A	p.Ala57Thr	missense_variant	2/12	2	NM_001010898.4	P1
SLC6A17-AS1	ENST00000430098.2	n.521C>T		non_coding_transcript_exon_variant	2/3	1
SLC6A17-AS1	ENST00000443008.1	n.506C>T		non_coding_transcript_exon_variant	2/2	3
SLC6A17-AS1	ENST00000418579.1	n.167C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50402 AN: 150100 Hom.: 10397 Cov.: 25

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.340

GnomAD3 exomes AF: 0.372 AC: 92386 AN: 248036 Hom.: 19083 AF XY: 0.383 AC XY: 51342 AN XY: 134016

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.453

Gnomad EAS exome AF: 0.210

Gnomad SAS exome AF: 0.346

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.433 AC: 632925 AN: 1460224 Hom.: 143349 Cov.: 72 AF XY: 0.433 AC XY: 314689 AN XY: 726238

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.534

Gnomad4 NFE exome AF: 0.462

Gnomad4 OTH exome AF: 0.419

GnomAD4 genome AF: 0.335 AC: 50386 AN: 150218 Hom.: 10392 Cov.: 25 AF XY: 0.338 AC XY: 24755 AN XY: 73240

Gnomad4 AFR AF: 0.0964

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.338

Alfa AF: 0.433 Hom.: 22848

Bravo AF: 0.308

TwinsUK AF: 0.452 AC: 1675

ALSPAC AF: 0.455 AC: 1754

ESP6500AA AF: 0.108 AC: 477

ESP6500EA AF: 0.445 AC: 3831

ExAC AF: 0.371 AC: 45076

Asia WGS AF: 0.268 AC: 935 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.000069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.083
Sift	Benign	0.55	T
Sift4G	Benign	0.44	T
Polyphen		0.049	B
Vest4		0.039
MPC		0.54
ClinPred		0.0035	T
GERP RS		2.6
Varity_R		0.027
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12737742; hg19: chr1-110709720; COSMIC: COSV58993671;