rs759833850

Positions:

• chr2-108010364-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_021815.5(SLC5A7):​c.1246G>A​(p.Val416Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000644 in 1,613,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SLC5A7 NM_021815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.35

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041014135).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000046 (7/152020) while in subpopulation SAS AF= 0.000622 (3/4824). AF 95% confidence interval is 0.000169. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A7	NM_021815.5	c.1246G>A	p.Val416Ile	missense_variant	9/9	ENST00000264047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A7	ENST00000264047.3	c.1246G>A	p.Val416Ile	missense_variant	9/9	1	NM_021815.5	P1
SLC5A7	ENST00000409059.5	c.1246G>A	p.Val416Ile	missense_variant	9/9	1		P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251358 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461722 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74240

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC5A7 protein function. ClinVar contains an entry for this variant (Variation ID: 580407). This variant has not been reported in the literature in individuals affected with SLC5A7-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 416 of the SLC5A7 protein (p.Val416Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.35
DEOGEN2	Benign	0.098	T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.37	N
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-1.5	N;N
MutationTaster	Benign	0.87	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.63	N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.079
MutPred		0.64		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.63
MPC		0.68
ClinPred		0.012	T
GERP RS		3.5
Varity_R		0.040
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs759833850; hg19: chr2-108626820; COSMIC: COSV50890378;