rs148535388

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_021815.5(SLC5A7):c.1306G>A(p.Val436Met) variant causes a missense change. The variant allele was found at a frequency of 0.000132 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V436L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SLC5A7
NM_021815.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 3.89

Publications

10 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 Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
congenital myasthenic syndrome 20
Inheritance: AR Classification: STRONG Submitted by: G2P, Ambry Genetics, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050662905).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000171 (26/152246) while in subpopulation AFR AF = 0.000409 (17/41570). AF 95% confidence interval is 0.00026. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A7	NM_021815.5 link	c.1306G>A	p.Val436Met	missense_variant	Exon 9 of 9	ENST00000264047.3	NP_068587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A7	ENST00000264047.3 link	c.1306G>A	p.Val436Met	missense_variant	Exon 9 of 9	1	NM_021815.5	ENSP00000264047.2
SLC5A7	ENST00000409059.5 link	c.1306G>A	p.Val436Met	missense_variant	Exon 9 of 9	1		ENSP00000387346.1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

251176

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1461652

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727120

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33462

American (AMR)

AF:

0.0000224

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.000353

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000136

AC:

151

AN:

1111908

Other (OTH)

AF:

0.0000994

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000171

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

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:

0.000114

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Apr 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC5A7 c.1306G>A; p.Val436Met variant (rs148535388), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 440281). This variant is observed in the general population with an overall allele frequency of 0.01% (31/282574 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.22). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Nov 02, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 06, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain:2

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 436 of the SLC5A7 protein (p.Val436Met). This variant is present in population databases (rs148535388, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with SLC5A7-related conditions. ClinVar contains an entry for this variant (Variation ID: 440281). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC5A7 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 21, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.87

.;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.051

T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

1.5

L;L

PhyloP100

3.9

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.22

Sift

Benign

0.051

T;T

Sift4G

Benign

0.069

T;T

Polyphen

0.042

B;B

Vest4

0.12

MVP

0.56

MPC

0.93

ClinPred

0.033

GERP RS

2.8

Varity_R

0.064

gMVP

0.57

Mutation Taster

=94/6

polymorphism

(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