10-49662648-ATA-GTT

Variant names:

• chr10-49662648-ATA-GTT
• NM_020549.5:c.1843_1845delATAinsGTT
• CHAT p.Ile615Val

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_020549.5(CHAT):​c.1843_1845delATAinsGTT​(p.Ile615Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1843_1845delATAinsGTT	p.Ile615Val	missense	N/A	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.1597_1599delATAinsGTT	p.Ile533Val	missense	N/A	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.1489_1491delATAinsGTT	p.Ile497Val	missense	N/A	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.1843_1845delATAinsGTT	p.Ile615Val	missense	N/A	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.1597_1599delATAinsGTT	p.Ile533Val	missense	N/A	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.1489_1491delATAinsGTT	p.Ile497Val	missense	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-50870694;