rs3731683

Variant names:

• chr2-108002084-G-A
• rs3731683
• NM_021815.5:c.741+44G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-108002084-G-A
• chr2-108002084-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021815.5(SLC5A7):​c.741+44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,573,448 control chromosomes in the GnomAD database, including 102,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14206 hom., cov: 32)
  • Exomes 𝑓: 0.35 (88281 hom.)
• Consequence: SLC5A7 NM_021815.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.707
• Publications: 11 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: Genomics England PanelApp, G2P, Ambry Genetics, PanelApp Australia, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-108002084-G-A is Benign according to our data. Variant chr2-108002084-G-A is described in ClinVar as Benign. ClinVar VariationId is 1242137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

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.741+44G>A		intron	N/A	NP_068587.1	Q9GZV3
	SLC5A7	NM_001305005.3		c.741+44G>A		intron	N/A	NP_001291934.1	Q9GZV3
	SLC5A7	NM_001305006.3		c.426+44G>A		intron	N/A	NP_001291935.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A7	ENST00000264047.3	TSL:1 MANE Select	c.741+44G>A		intron	N/A	ENSP00000264047.2	Q9GZV3
	SLC5A7	ENST00000409059.5	TSL:1	c.741+44G>A		intron	N/A	ENSP00000387346.1	Q9GZV3
	SLC5A7	ENST00000950055.1		c.627+44G>A		intron	N/A	ENSP00000620114.1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63900 AN: 151974 Hom.: 14171 Cov.: 32

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.421

GnomAD2 exomes AF: 0.366 AC: 85436 AN: 233320 AF XY: 0.355

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.475

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.347 AC: 493887 AN: 1421356 Hom.: 88281 Cov.: 28 AF XY: 0.344 AC XY: 241439 AN XY: 702068

African (AFR) AF: 0.581 AC: 18508 AN: 31830

American (AMR) AF: 0.469 AC: 18608 AN: 39708

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 7635 AN: 24820

East Asian (EAS) AF: 0.279 AC: 10880 AN: 38948

South Asian (SAS) AF: 0.248 AC: 20350 AN: 82106

European-Finnish (FIN) AF: 0.435 AC: 22991 AN: 52820

Middle Eastern (MID) AF: 0.315 AC: 1673 AN: 5308

European-Non Finnish (NFE) AF: 0.343 AC: 372969 AN: 1087386

Other (OTH) AF: 0.347 AC: 20273 AN: 58430

GnomAD4 genome AF: 0.421 AC: 63973 AN: 152092 Hom.: 14206 Cov.: 32 AF XY: 0.424 AC XY: 31523 AN XY: 74348

African (AFR) AF: 0.569 AC: 23614 AN: 41486

American (AMR) AF: 0.459 AC: 7013 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1075 AN: 3470

East Asian (EAS) AF: 0.253 AC: 1304 AN: 5162

South Asian (SAS) AF: 0.238 AC: 1149 AN: 4828

European-Finnish (FIN) AF: 0.457 AC: 4830 AN: 10566

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23544 AN: 67974

Other (OTH) AF: 0.416 AC: 879 AN: 2112

Alfa AF: 0.358 Hom.: 19519

Bravo AF: 0.429

Asia WGS AF: 0.279 AC: 971 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Congenital myasthenic syndrome 20 (1)
-	-	1	Neuronopathy, distal hereditary motor, type 7A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.15
DANN	Benign	0.61
PhyloP100		-0.71
Mutation Taster		=99/1	polymorphism (auto)

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: rs3731683; hg19: chr2-108618540; COSMIC: COSV50902791;