Genetic Variant NM_001024845.3:c.319+51C>T (chr1-44009914-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001024845.3(SLC6A9):c.319+51C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0869 in 1,594,426 control chromosomes in the GnomAD database, including 7,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1409 hom., cov: 32)

Exomes 𝑓: 0.083 ( 6138 hom. )

Consequence

SLC6A9
NM_001024845.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.620

Publications

14 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: AR, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 1-44009914-G-A is Benign according to our data. Variant chr1-44009914-G-A is described in ClinVar as Benign. ClinVar VariationId is 1232090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A9	NM_001024845.3 link	c.319+51C>T		intron_variant	Intron 4 of 13	ENST00000372310.8	NP_001020016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A9	ENST00000372310.8 link	c.319+51C>T		intron_variant	Intron 4 of 13	5	NM_001024845.3	ENSP00000361384.4		P48067-2

Frequencies

GnomAD3 genomes

AF:

0.120

AC:

18238

AN:

152092

Hom.:

1407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.0726

Gnomad EAS

AF:

0.168

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.0670

Gnomad OTH

AF:

0.116

GnomAD2 exomes

AF:

0.109

AC:

25989

AN:

239514

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.209

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.0737

Gnomad EAS exome

AF:

0.160

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.0714

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.0834

AC:

120224

AN:

1442214

Hom.:

6138

Cov.:

AF XY:

0.0833

AC XY:

59627

AN XY:

715996

show subpopulations

African (AFR)

AF:

0.212

AC:

6932

AN:

32768

American (AMR)

AF:

0.150

AC:

6460

AN:

42970

Ashkenazi Jewish (ASJ)

AF:

0.0729

AC:

1824

AN:

25036

East Asian (EAS)

AF:

0.204

AC:

8035

AN:

39402

South Asian (SAS)

AF:

0.115

AC:

9644

AN:

83820

European-Finnish (FIN)

AF:

0.114

AC:

6018

AN:

52614

Middle Eastern (MID)

AF:

0.132

AC:

694

AN:

5256

European-Non Finnish (NFE)

AF:

0.0682

AC:

75038

AN:

1100986

Other (OTH)

AF:

0.0940

AC:

5579

AN:

59362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

5154

10308

15463

20617

25771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3070

6140

9210

12280

15350

<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:

0.120

AC:

18256

AN:

152212

Hom.:

1409

Cov.:

AF XY:

0.121

AC XY:

9035

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.206

AC:

8562

AN:

41518

American (AMR)

AF:

0.122

AC:

1865

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0726

AC:

252

AN:

3470

East Asian (EAS)

AF:

0.168

AC:

866

AN:

5152

South Asian (SAS)

AF:

0.106

AC:

512

AN:

4828

European-Finnish (FIN)

AF:

0.125

AC:

1323

AN:

10600

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0670

AC:

4557

AN:

68024

Other (OTH)

AF:

0.115

AC:

242

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

789

1579

2368

3158

3947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.0870

Hom.:

2184

Bravo

AF:

0.125

Asia WGS

AF:

0.129

AC:

448

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 16, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.5

(source)

DANN

Benign

0.54

PhyloP100

0.62

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over