rs3810950

Variant names:

• chr10-49616573-G-A
• rs3810950
• NM_020549.5:c.358G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-49616573-G-A
• chr10-49616573-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_020549.5(CHAT):​c.358G>A​(p.Ala120Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,610,550 control chromosomes in the GnomAD database, including 47,769 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3040 hom., cov: 33)
  • Exomes 𝑓: 0.24 (44729 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.34
• Publications: 69 publications found

Genes affected

CHAT (HGNC:1912): (choline O-acetyltransferase) This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]

CHAT Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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 (MetaRNN=0.003578037).
• BP6: Variant 10-49616573-G-A is Benign according to our data. Variant chr10-49616573-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020549.5. 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
	CHAT	NM_020549.5	MANE Select	c.358G>A	p.Ala120Thr	missense	Exon 2 of 15	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.112G>A	p.Ala38Thr	missense	Exon 3 of 16	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.4G>A	p.Ala2Thr	missense	Exon 2 of 15	NP_001136401.2	P28329-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.358G>A	p.Ala120Thr	missense	Exon 2 of 15	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.112G>A	p.Ala38Thr	missense	Exon 3 of 16	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.4G>A	p.Ala2Thr	missense	Exon 2 of 15	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27291 AN: 152026 Hom.: 3042 Cov.: 33

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.207 AC: 51237 AN: 247220 AF XY: 0.218

Gnomad AFR exome AF: 0.0412

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.243 AC: 354143 AN: 1458404 Hom.: 44729 Cov.: 33 AF XY: 0.245 AC XY: 177619 AN XY: 725372

African (AFR) AF: 0.0391 AC: 1307 AN: 33398

American (AMR) AF: 0.149 AC: 6638 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6407 AN: 26094

East Asian (EAS) AF: 0.173 AC: 6848 AN: 39574

South Asian (SAS) AF: 0.276 AC: 23678 AN: 85806

European-Finnish (FIN) AF: 0.186 AC: 9899 AN: 53286

Middle Eastern (MID) AF: 0.279 AC: 1608 AN: 5766

European-Non Finnish (NFE) AF: 0.256 AC: 283627 AN: 1109676

Other (OTH) AF: 0.235 AC: 14131 AN: 60230

GnomAD4 genome AF: 0.179 AC: 27284 AN: 152146 Hom.: 3040 Cov.: 33 AF XY: 0.179 AC XY: 13322 AN XY: 74342

African (AFR) AF: 0.0482 AC: 2002 AN: 41566

American (AMR) AF: 0.185 AC: 2822 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 812 AN: 3470

East Asian (EAS) AF: 0.157 AC: 814 AN: 5170

South Asian (SAS) AF: 0.273 AC: 1310 AN: 4806

European-Finnish (FIN) AF: 0.182 AC: 1923 AN: 10588

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16891 AN: 67944

Other (OTH) AF: 0.190 AC: 401 AN: 2108

Alfa AF: 0.229 Hom.: 16272

Bravo AF: 0.171

TwinsUK AF: 0.257 AC: 953

ALSPAC AF: 0.273 AC: 1054

ESP6500AA AF: 0.0517 AC: 228

ESP6500EA AF: 0.249 AC: 2144

ExAC AF: 0.207 AC: 25173

Asia WGS AF: 0.191 AC: 664 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Familial infantile myasthenia (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.10
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.014	B
Vest4		0.22
MPC		0.24
ClinPred		0.0033	T
GERP RS		3.0
Varity_R		0.026
gMVP		0.17
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3810950; hg19: chr10-50824619; COSMIC: COSV60321229; COSMIC: COSV60321229;