rs17279437

chr3-45772602-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The NM_020208.4(SLC6A20):c.596C>T(p.Thr199Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0894 in 1,612,876 control chromosomes in the GnomAD database, including 7,209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (424 hom., cov: 32)
  • Exomes 𝑓: 0.092 (6785 hom.)
• Consequence: SLC6A20 NM_020208.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 8.14

Genes affected

SLC6A20 (HGNC:30927): (solute carrier family 6 member 20) Transport of small hydrophilic substances across cell membranes is mediated by substrate-specific transporter proteins which have been classified into several families of related genes. The protein encoded by this gene belongs to the sodium:neurotransmitter symporter (SNF) family and functions as a proline transporter expressed in kidney and small intestine. Mutations in this gene are associated with Hyperglycinuria and Iminoglycinuria. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, BayesDel_addAF, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.006226331).
• BP6: Variant 3-45772602-G-A is Benign according to our data. Variant chr3-45772602-G-A is described in ClinVar as [Benign]. Clinvar id is 4845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45772602-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC6A20	NM_020208.4	c.596C>T	p.Thr199Met	missense_variant	5/11	ENST00000358525.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC6A20	ENST00000358525.9	c.596C>T	p.Thr199Met	missense_variant	5/11	1	NM_020208.4	P1
SLC6A20	ENST00000353278.8	c.583-1144C>T		intron_variant		1
SLC6A20	ENST00000703343.1	c.596C>T	p.Thr199Met	missense_variant	5/11
SLC6A20	ENST00000413781.1	n.571C>T		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.0659 AC: 10025 AN: 152124 Hom.: 424 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.00654

Gnomad SAS AF: 0.0394

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0976

Gnomad OTH AF: 0.0492

GnomAD3 exomes AF: 0.0717 AC: 17750 AN: 247566 Hom.: 744 AF XY: 0.0726 AC XY: 9748 AN XY: 134334

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.0466

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.00491

Gnomad SAS exome AF: 0.0383

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0967

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0918 AC: 134120 AN: 1460634 Hom.: 6785 Cov.: 31 AF XY: 0.0903 AC XY: 65619 AN XY: 726600

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.0471

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.00912

Gnomad4 SAS exome AF: 0.0404

Gnomad4 FIN exome AF: 0.0997

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.0799

GnomAD4 genome AF: 0.0659 AC: 10030 AN: 152242 Hom.: 424 Cov.: 32 AF XY: 0.0648 AC XY: 4826 AN XY: 74426

Gnomad4 AFR AF: 0.0188

Gnomad4 AMR AF: 0.0499

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.00656

Gnomad4 SAS AF: 0.0396

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.0976

Gnomad4 OTH AF: 0.0487

Alfa AF: 0.0853 Hom.: 1308

Bravo AF: 0.0596

TwinsUK AF: 0.0909 AC: 337

ALSPAC AF: 0.102 AC: 392

ESP6500AA AF: 0.0204 AC: 85

ESP6500EA AF: 0.0994 AC: 837

ExAC AF: 0.0702 AC: 8496

Asia WGS AF: 0.0270 AC: 97 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperglycinuria Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Affects, no assertion criteria provided	literature only	OMIM	Dec 01, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

SLC6A20-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

This variant is associated with the following publications: (PMID: 19033659, 21572414) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	4.2	H;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.58
MPC		0.88
ClinPred		0.079	T
GERP RS		5.3
Varity_R		0.84
gMVP		0.83

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: rs17279437; hg19: chr3-45814094; COSMIC: COSV62072026; COSMIC: COSV62072026;