chr2-108012648-G-A

Variant names:

• chr2-108012648-G-A
• rs333227
• NM_021815.5:c.*1787G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021815.5(SLC5A7):​c.*1787G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.898 in 152,150 control chromosomes in the GnomAD database, including 61,556 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.90 (61556 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: SLC5A7 NM_021815.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0430
• 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 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A7	NM_021815.5	c.*1787G>A		3_prime_UTR_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	c.*1787G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_021815.5	ENSP00000264047.2

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136479 AN: 152032 Hom.: 61491 Cov.: 32

Gnomad AFR AF: 0.949

Gnomad AMI AF: 0.846

Gnomad AMR AF: 0.911

Gnomad ASJ AF: 0.783

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.948

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.858

Gnomad OTH AF: 0.880

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.898 AC: 136604 AN: 152150 Hom.: 61556 Cov.: 32 AF XY: 0.902 AC XY: 67120 AN XY: 74380

African (AFR) AF: 0.949 AC: 39418 AN: 41548

American (AMR) AF: 0.911 AC: 13902 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 2715 AN: 3468

East Asian (EAS) AF: 0.994 AC: 5134 AN: 5166

South Asian (SAS) AF: 0.875 AC: 4210 AN: 4812

European-Finnish (FIN) AF: 0.948 AC: 10048 AN: 10600

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.858 AC: 58310 AN: 67980

Other (OTH) AF: 0.881 AC: 1860 AN: 2112

Alfa AF: 0.865 Hom.: 65585

Bravo AF: 0.899

Asia WGS AF: 0.937 AC: 3249 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.60
DANN	Benign	0.29
PhyloP100		-0.043
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs333227; hg19: chr2-108629104;