NM_021815.5:c.1630C>T

Variant names:

• chr2-108010748-C-T
• rs780371731
• NM_021815.5:c.1630C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_021815.5(SLC5A7):​c.1630C>T​(p.Leu544Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SLC5A7 NM_021815.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.69
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14224234).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A7	NM_021815.5	MANE Select	c.1630C>T	p.Leu544Phe	missense	Exon 9 of 9	NP_068587.1	Q9GZV3
	SLC5A7	NM_001305005.3		c.1630C>T	p.Leu544Phe	missense	Exon 9 of 9	NP_001291934.1	Q9GZV3
	SLC5A7	NM_001305006.3		c.1315C>T	p.Leu439Phe	missense	Exon 8 of 8	NP_001291935.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A7	ENST00000264047.3	TSL:1 MANE Select	c.1630C>T	p.Leu544Phe	missense	Exon 9 of 9	ENSP00000264047.2	Q9GZV3
	SLC5A7	ENST00000409059.5	TSL:1	c.1630C>T	p.Leu544Phe	missense	Exon 9 of 9	ENSP00000387346.1	Q9GZV3
	SLC5A7	ENST00000950055.1		c.1516C>T	p.Leu506Phe	missense	Exon 8 of 8	ENSP00000620114.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250850 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461442 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111840

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Neuronopathy, distal hereditary motor, type 7A (1)
-	1	-	Neuronopathy, distal hereditary motor, type 7A;C4310694:Congenital myasthenic syndrome 20 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.39
Sift	Benign	0.70	T
Sift4G	Benign	0.70	T
Polyphen		0.082	B
Vest4		0.15
MutPred		0.29		Gain of loop (P = 0.0312)
MVP		0.83
MPC		0.047
ClinPred		0.21	T
GERP RS		6.0
Varity_R		0.20
gMVP		0.27
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs780371731; hg19: chr2-108627204;