10-49613145-G-T

Variant names:

• chr10-49613145-G-T
• rs3729496
• ENST00000460699.5:n.38G>T

Variant summary

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

The ENST00000460699.5(CHAT):​n.38G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 152,156 control chromosomes in the GnomAD database, including 28,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (28178 hom., cov: 33)
  • Exomes 𝑓: 0.70 (21 hom.)
• Consequence: CHAT ENST00000460699.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00500
• 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=-0.81).
• BP6: Variant 10-49613145-G-T is Benign according to our data. Variant chr10-49613145-G-T is described in ClinVar as Benign. ClinVar VariationId is 1255202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020985.4	c.-298G>T		5_prime_UTR_variant	Exon 1 of 16		NP_066265.4
CHAT	NM_020986.4	c.-126G>T		5_prime_UTR_variant	Exon 1 of 15		NP_066266.4
CHAT	NM_020984.4	c.-68-3357G>T		intron_variant	Intron 1 of 14		NP_066264.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000460699.5	n.38G>T		non_coding_transcript_exon_variant	Exon 1 of 7	1
CHAT	ENST00000481336.5	n.27G>T		non_coding_transcript_exon_variant	Exon 1 of 3	1
CHAT	ENST00000339797.5	c.-68-3357G>T		intron_variant	Intron 1 of 14	1		ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83799 AN: 151952 Hom.: 28193 Cov.: 33

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.778

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.312

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.664

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.765

Gnomad OTH AF: 0.592

GnomAD4 exome AF: 0.698 AC: 60 AN: 86 Hom.: 21 Cov.: 0 AF XY: 0.734 AC XY: 47 AN XY: 64

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.333 AC: 2 AN: 6

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AF: 1.00 AC: 4 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 48 AN: 64

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.551 AC: 83770 AN: 152070 Hom.: 28178 Cov.: 33 AF XY: 0.548 AC XY: 40768 AN XY: 74348

African (AFR) AF: 0.176 AC: 7284 AN: 41486

American (AMR) AF: 0.498 AC: 7615 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2421 AN: 3468

East Asian (EAS) AF: 0.312 AC: 1605 AN: 5152

South Asian (SAS) AF: 0.759 AC: 3660 AN: 4822

European-Finnish (FIN) AF: 0.664 AC: 7024 AN: 10578

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.765 AC: 52022 AN: 67966

Other (OTH) AF: 0.587 AC: 1238 AN: 2110

Alfa AF: 0.669 Hom.: 84337

Bravo AF: 0.511

Asia WGS AF: 0.493 AC: 1717 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Oct 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.88
PhyloP100		0.0050
PromoterAI		-0.023	Neutral
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: rs3729496; hg19: chr10-50821191;