2-107988181-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_021815.5(SLC5A7):c.26T>C(p.Ile9Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I9V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SLC5A7 NM_021815.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3046952).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000753 (11/1461648) while in subpopulation EAS AF= 0.000202 (8/39694). AF 95% confidence interval is 0.0000993. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 30. 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.26T>C	p.Ile9Thr	missense_variant	2/9	ENST00000264047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A7	ENST00000264047.3	c.26T>C	p.Ile9Thr	missense_variant	2/9	1	NM_021815.5	P1
SLC5A7	ENST00000409059.5	c.26T>C	p.Ile9Thr	missense_variant	2/9	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251430 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461648 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Aug 17, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 9 of the SLC5A7 protein (p.Ile9Thr). This variant is present in population databases (rs543338077, gnomAD 0.03%). 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: 1021994). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;D
Eigen	Benign	0.039
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.055	T;T
Polyphen		0.020	B;B
Vest4		0.48
MutPred		0.65		Gain of disorder (P = 0.0262);Gain of disorder (P = 0.0262);
MVP		0.80
MPC		1.1
ClinPred		0.32	T
GERP RS		5.7
Varity_R		0.21
gMVP		0.73

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: rs543338077; hg19: chr2-108604637;