10-49614146-G-C

Variant names:

• chr10-49614146-G-C
• rs7903315
• NM_020549.5:c.-44G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020549.5(CHAT):​c.-44G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,545,460 control chromosomes in the GnomAD database, including 414,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (28226 hom., cov: 25)
  • Exomes 𝑓: 0.73 (386585 hom.)
• Consequence: CHAT NM_020549.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.494

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-49614146-G-C is Benign according to our data. Variant chr10-49614146-G-C is described in ClinVar as [Benign]. Clinvar id is 261325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.-44G>C		5_prime_UTR_variant	Exon 1 of 15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653	c.-44G>C		5_prime_UTR_variant	Exon 1 of 15	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.554 AC: 83524 AN: 150778 Hom.: 28240 Cov.: 25

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.686

Gnomad NFE AF: 0.768

Gnomad OTH AF: 0.596

GnomAD3 exomes AF: 0.630 AC: 89439 AN: 142068 Hom.: 31117 AF XY: 0.656 AC XY: 50419 AN XY: 76844

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.705

Gnomad EAS exome AF: 0.295

Gnomad SAS exome AF: 0.785

Gnomad FIN exome AF: 0.665

Gnomad NFE exome AF: 0.771

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.733 AC: 1022741 AN: 1394564 Hom.: 386585 Cov.: 46 AF XY: 0.738 AC XY: 507830 AN XY: 687670

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.702

Gnomad4 EAS exome AF: 0.372

Gnomad4 SAS exome AF: 0.787

Gnomad4 FIN exome AF: 0.666

Gnomad4 NFE exome AF: 0.775

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.553 AC: 83496 AN: 150896 Hom.: 28226 Cov.: 25 AF XY: 0.551 AC XY: 40565 AN XY: 73628

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.502

Gnomad4 ASJ AF: 0.702

Gnomad4 EAS AF: 0.320

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.768

Gnomad4 OTH AF: 0.590

Alfa AF: 0.619 Hom.: 4227

Bravo AF: 0.514

Asia WGS AF: 0.503 AC: 1753 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Feb 01, 2016

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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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial infantile myasthenia Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

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	-0.81
CADD	Benign	1.5
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs7903315; hg19: chr10-50822192;