NM_021815.5:c.1245C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_021815.5(SLC5A7):c.1245C>T(p.Ile415Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,613,898 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 15 hom. )

Consequence

SLC5A7
NM_021815.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.73

Publications

2 publications found

Variant links:

Genes affected

SLC5A7 (HGNC:14025): (solute carrier family 5 member 7) This gene encodes a sodium ion- and chloride ion-dependent high-affinity transporter that mediates choline uptake for acetylcholine synthesis in cholinergic neurons. The protein transports choline from the extracellular space into presynaptic terminals for synthesis into acetylcholine. Increased choline uptake results from increased density of this protein in synaptosomal plasma membranes in response to depolarization of cholinergic terminals. Dysfunction of cholinergic signaling has been implicated in various disorders including depression, attention-deficit disorder, and schizophrenia. An allelic variant of this gene is associated with autosomal dominant distal hereditary motor neuronopathy type VIIA. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

SLC5A7 Gene-Disease associations (from GenCC):

neuronopathy, distal hereditary motor, type 7A
Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, PanelApp Australia
congenital myasthenic syndrome 20
Inheritance: AR Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
distal hereditary motor neuropathy type 7
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SLC5A7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 2-108010363-C-T is Benign according to our data. Variant chr2-108010363-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 464171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00755 (1149/152174) while in subpopulation AFR AF = 0.0254 (1055/41526). AF 95% confidence interval is 0.0241. There are 17 homozygotes in GnomAd4. There are 533 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021815.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC5A7	NM_021815.5	MANE Select	c.1245C>T	p.Ile415Ile	synonymous	Exon 9 of 9	NP_068587.1	Q9GZV3
SLC5A7	NM_001305005.3		c.1245C>T	p.Ile415Ile	synonymous	Exon 9 of 9	NP_001291934.1	Q9GZV3
SLC5A7	NM_001305006.3		c.930C>T	p.Ile310Ile	synonymous	Exon 8 of 8	NP_001291935.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC5A7	ENST00000264047.3	TSL:1 MANE Select	c.1245C>T	p.Ile415Ile	synonymous	Exon 9 of 9	ENSP00000264047.2	Q9GZV3
SLC5A7	ENST00000409059.5	TSL:1	c.1245C>T	p.Ile415Ile	synonymous	Exon 9 of 9	ENSP00000387346.1	Q9GZV3
SLC5A7	ENST00000950055.1		c.1131C>T	p.Ile377Ile	synonymous	Exon 8 of 8	ENSP00000620114.1

Frequencies

GnomAD3 genomes

AF:

0.00754

AC:

1146

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00420

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00204

AC:

513

AN:

251366

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.0266

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000835

AC:

1221

AN:

1461724

Hom.:

Cov.:

AF XY:

0.000734

AC XY:

534

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0269

AC:

901

AN:

33466

American (AMR)

AF:

0.00172

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000104

AC:

116

AN:

1111914

Other (OTH)

AF:

0.00194

AC:

117

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

152

228

304

380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00755

AC:

1149

AN:

152174

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

533

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0254

AC:

1055

AN:

41526

American (AMR)

AF:

0.00419

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000831

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68000

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00338

Hom.:

Bravo

AF:

0.00874

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Neuronopathy, distal hereditary motor, type 7A;C4310694:Congenital myasthenic syndrome 20 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

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