NM_020549.5:c.-44G>C

Variant names:

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

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.-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
• Publications: 11 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 (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 VariationId 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.

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.-44G>C		5_prime_UTR	Exon 1 of 15	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.-360G>C		5_prime_UTR	Exon 1 of 16	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.-398G>C		5_prime_UTR	Exon 1 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.-44G>C		5_prime_UTR	Exon 1 of 15	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.-360G>C		5_prime_UTR	Exon 1 of 16	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.-68-2356G>C		intron	N/A	ENSP00000343486.1	P28329-3

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

GnomAD2 exomes AF: 0.630 AC: 89439 AN: 142068 AF XY: 0.656

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 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

African (AFR) AF: 0.157 AC: 4958 AN: 31520

American (AMR) AF: 0.410 AC: 14646 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 17680 AN: 25168

East Asian (EAS) AF: 0.372 AC: 13289 AN: 35718

South Asian (SAS) AF: 0.787 AC: 62275 AN: 79134

European-Finnish (FIN) AF: 0.666 AC: 31331 AN: 47012

Middle Eastern (MID) AF: 0.730 AC: 2995 AN: 4104

European-Non Finnish (NFE) AF: 0.775 AC: 836201 AN: 1078448

Other (OTH) AF: 0.681 AC: 39366 AN: 57778

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

African (AFR) AF: 0.175 AC: 7206 AN: 41170

American (AMR) AF: 0.502 AC: 7605 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2437 AN: 3470

East Asian (EAS) AF: 0.320 AC: 1613 AN: 5038

South Asian (SAS) AF: 0.783 AC: 3685 AN: 4704

European-Finnish (FIN) AF: 0.660 AC: 6832 AN: 10352

Middle Eastern (MID) AF: 0.672 AC: 195 AN: 290

European-Non Finnish (NFE) AF: 0.768 AC: 51987 AN: 67716

Other (OTH) AF: 0.590 AC: 1236 AN: 2094

Alfa AF: 0.619 Hom.: 4227

Bravo AF: 0.514

Asia WGS AF: 0.503 AC: 1753 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Familial infantile myasthenia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.5
DANN	Benign	0.71
PhyloP100		-0.49
PromoterAI		0.030	Neutral
Mutation Taster		=300/0	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: rs7903315; hg19: chr10-50822192;