rs1013940

chr2-107992192-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_021815.5(SLC5A7):c.265A>G(p.Ile89Val) variant causes a missense change. The variant allele was found at a frequency of 0.0844 in 1,612,352 control chromosomes in the GnomAD database, including 6,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I89T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.075 (582 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6067 hom.)
• Consequence: SLC5A7 NM_021815.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.23

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a mutagenesis_site Only 20% of wild-type choline uptake activity. (size 0) in uniprot entity SC5A7_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.002653569).
• BP6: Variant 2-107992192-A-G is Benign according to our data. Variant chr2-107992192-A-G is described in ClinVar as [Benign]. Clinvar id is 261428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-107992192-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A7	NM_021815.5	c.265A>G	p.Ile89Val	missense_variant	3/9	ENST00000264047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A7	ENST00000264047.3	c.265A>G	p.Ile89Val	missense_variant	3/9	1	NM_021815.5	P1
SLC5A7	ENST00000409059.5	c.265A>G	p.Ile89Val	missense_variant	3/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 11415 AN: 152192 Hom.: 578 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0829

Gnomad OTH AF: 0.0628

GnomAD3 exomes AF: 0.0926 AC: 23270 AN: 251232 Hom.: 1482 AF XY: 0.0865 AC XY: 11750 AN XY: 135816

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.0517

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.0288

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.0798

Gnomad OTH exome AF: 0.0842

GnomAD4 exome AF: 0.0854 AC: 124643 AN: 1460042 Hom.: 6067 Cov.: 29 AF XY: 0.0834 AC XY: 60568 AN XY: 726466

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.0506

Gnomad4 EAS exome AF: 0.127

Gnomad4 SAS exome AF: 0.0286

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0858

Gnomad4 OTH exome AF: 0.0756

GnomAD4 genome AF: 0.0750 AC: 11421 AN: 152310 Hom.: 582 Cov.: 32 AF XY: 0.0767 AC XY: 5711 AN XY: 74456

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.0329

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.0829

Gnomad4 OTH AF: 0.0621

Alfa AF: 0.0778 Hom.: 642

Bravo AF: 0.0778

TwinsUK AF: 0.0868 AC: 322

ALSPAC AF: 0.0960 AC: 370

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.0814 AC: 700

ExAC AF: 0.0839 AC: 10192

Asia WGS AF: 0.0740 AC: 258 AN: 3478

EpiCase AF: 0.0776

EpiControl AF: 0.0687

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	This variant is associated with the following publications: (PMID: 12237312) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	19
Dann	Benign	0.70
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N;N
MutationTaster	Benign	0.0013	P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.44	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.44	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.015	B;B
Vest4		0.045
MPC		0.70
ClinPred		0.012	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs1013940; hg19: chr2-108608648; COSMIC: COSV50889485;