rs41313405

Positions:

• chr1-110198296-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001010898.4(SLC6A17):​c.2036A>G​(p.Lys679Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0039 in 1,614,160 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (44 hom.)
• Consequence: SLC6A17 NM_001010898.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.75

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC6A17. . Gene score misZ 2.3852 (greater than the threshold 3.09). Trascript score misZ 3.6036 (greater than threshold 3.09). GenCC has associacion of gene with progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, schizophrenia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035065114).
• BP6: Variant 1-110198296-A-G is Benign according to our data. Variant chr1-110198296-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 376873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC6A17	NM_001010898.4	c.2036A>G	p.Lys679Arg	missense_variant	12/12	ENST00000331565.5	NP_001010898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC6A17	ENST00000331565.5	c.2036A>G	p.Lys679Arg	missense_variant	12/12	2	NM_001010898.4	ENSP00000330199.3

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 872 AN: 152156 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0373

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00561 AC: 1410 AN: 251398 Hom.: 15 AF XY: 0.00553 AC XY: 751 AN XY: 135874

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00371 AC: 5419 AN: 1461886 Hom.: 44 Cov.: 33 AF XY: 0.00381 AC XY: 2772 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0297

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00573 AC: 872 AN: 152274 Hom.: 7 Cov.: 33 AF XY: 0.00685 AC XY: 510 AN XY: 74444

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0373

Gnomad4 NFE AF: 0.00610

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00475 Hom.: 8

Bravo AF: 0.00253

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00534 AC: 648

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC6A17: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.079
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.14
Sift	Uncertain	0.025	D
Sift4G	Benign	0.14	T
Polyphen		0.0090	B
Vest4		0.14
MVP		0.72
MPC		0.47
ClinPred		0.014	T
GERP RS		4.4
Varity_R		0.15
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs41313405; hg19: chr1-110740918;