rs868750

Variant names:

• chr10-49625793-G-A
• rs868750
• NM_020549.5:c.933+140G>A

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.933+140G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 874,318 control chromosomes in the GnomAD database, including 11,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1527 hom., cov: 32)
  • Exomes 𝑓: 0.16 (9892 hom.)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.407
• Publications: 12 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: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.91).
• BP6: Variant 10-49625793-G-A is Benign according to our data. Variant chr10-49625793-G-A is described in ClinVar as [Benign]. Clinvar id is 680208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.933+140G>A		intron_variant	Intron 6 of 14	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.933+140G>A		intron_variant	Intron 6 of 14	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19570 AN: 152080 Hom.: 1528 Cov.: 32

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0693

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.161 AC: 116279 AN: 722120 Hom.: 9892 AF XY: 0.163 AC XY: 61312 AN XY: 376804

African (AFR) AF: 0.0304 AC: 579 AN: 19018

American (AMR) AF: 0.111 AC: 3755 AN: 33958

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 2857 AN: 20074

East Asian (EAS) AF: 0.0811 AC: 2644 AN: 32620

South Asian (SAS) AF: 0.171 AC: 10907 AN: 63650

European-Finnish (FIN) AF: 0.155 AC: 5257 AN: 33916

Middle Eastern (MID) AF: 0.189 AC: 759 AN: 4012

European-Non Finnish (NFE) AF: 0.176 AC: 84176 AN: 478984

Other (OTH) AF: 0.149 AC: 5345 AN: 35888

GnomAD4 genome AF: 0.128 AC: 19556 AN: 152198 Hom.: 1527 Cov.: 32 AF XY: 0.126 AC XY: 9370 AN XY: 74422

African (AFR) AF: 0.0334 AC: 1389 AN: 41536

American (AMR) AF: 0.119 AC: 1818 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3470

East Asian (EAS) AF: 0.0688 AC: 356 AN: 5172

South Asian (SAS) AF: 0.166 AC: 802 AN: 4818

European-Finnish (FIN) AF: 0.145 AC: 1533 AN: 10600

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12537 AN: 67992

Other (OTH) AF: 0.139 AC: 293 AN: 2112

Alfa AF: 0.167 Hom.: 4188

Bravo AF: 0.120

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.90
DANN	Benign	0.49
PhyloP100		0.41
Mutation Taster		=100/0	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: rs868750; hg19: chr10-50833839;