Genetic Variant SLC6A9:c.1537-6G>A (chr1-43998031-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001024845.3(SLC6A9):c.1537-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,607,960 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

SLC6A9
NM_001024845.3 splice_region, intron

Scores

Splicing: ADA: 0.00007098

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.05

Publications

1 publications found

Variant links:

Genes affected

SLC6A9 (HGNC:11056): (solute carrier family 6 member 9) The amino acid glycine acts as an inhibitory neurotransmitter in the central nervous system. The protein encoded by this gene is one of two transporters that stop glycine signaling by removing it from the synaptic cleft. [provided by RefSeq, Jun 2016]

SLC6A9 Gene-Disease associations (from GenCC):

atypical glycine encephalopathy
Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen
infantile glycine encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC6A9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-43998031-C-T is Benign according to our data. Variant chr1-43998031-C-T is described in ClinVar as Benign. ClinVar VariationId is 476371.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00243 (370/152280) while in subpopulation AFR AF = 0.00794 (330/41560). AF 95% confidence interval is 0.00724. There are 3 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024845.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC6A9	NM_001024845.3	MANE Select	c.1537-6G>A	splice_region intron	N/A	NP_001020016.1	P48067-2
SLC6A9	NM_201649.4		c.1756-6G>A	splice_region intron	N/A	NP_964012.2	P48067-1
SLC6A9	NM_006934.4		c.1594-6G>A	splice_region intron	N/A	NP_008865.2	P48067-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC6A9	ENST00000372310.8	TSL:5 MANE Select	c.1537-6G>A	splice_region intron	N/A	ENSP00000361384.4	P48067-2
SLC6A9	ENST00000360584.6	TSL:1	c.1756-6G>A	splice_region intron	N/A	ENSP00000353791.2	P48067-1
SLC6A9	ENST00000357730.6	TSL:1	c.1594-6G>A	splice_region intron	N/A	ENSP00000350362.2	P48067-3

Frequencies

GnomAD3 genomes

AF:

0.00243

AC:

370

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.000680

AC:

167

AN:

245686

AF XY:

0.000528

show subpopulations

Gnomad AFR exome

AF:

0.00698

Gnomad AMR exome

AF:

0.000702

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.000323

AC:

470

AN:

1455680

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

210

AN XY:

723530

show subpopulations

African (AFR)

AF:

0.00644

AC:

215

AN:

33378

American (AMR)

AF:

0.000834

AC:

AN:

44358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25664

East Asian (EAS)

AF:

0.00184

AC:

AN:

39576

South Asian (SAS)

AF:

0.0000936

AC:

AN:

85450

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53198

Middle Eastern (MID)

AF:

0.000699

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000731

AC:

AN:

1108192

Other (OTH)

AF:

0.000865

AC:

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00243

AC:

370

AN:

152280

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

176

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00794

AC:

330

AN:

41560

American (AMR)

AF:

0.00144

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000773

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68020

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000840

Hom.:

Bravo

AF:

0.00253

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Atypical glycine encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.8

(source)

DANN

Benign

0.84

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000071

dbscSNV1_RF

Benign

0.024

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: -16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over