rs4838544

Variant names:

• chr10-49648606-G-A
• rs4838544
• NM_020549.5:c.1381G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-49648606-G-A
• chr10-49648606-G-T
• chr10-49648606-G-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.1381G>A​(p.Val461Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.994 in 1,609,818 control chromosomes in the GnomAD database, including 795,386 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V461A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.97 (71526 hom., cov: 32)
  • Exomes 𝑓: 1.0 (723860 hom.)
• Consequence: CHAT NM_020549.5 missense, splice_region
• Scores: Splicing: ADA: 0.00002959
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.30
• Publications: 28 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 (MetaRNN=6.5965037E-7).
• BP6: Variant 10-49648606-G-A is Benign according to our data. Variant chr10-49648606-G-A is described in ClinVar as Benign. ClinVar VariationId is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.1381G>A	p.Val461Met	missense splice_region	Exon 9 of 15	NP_065574.4	P28329-1
	CHAT	NM_001142933.2		c.1135G>A	p.Val379Met	missense splice_region	Exon 10 of 16	NP_001136405.2	P28329-2
	CHAT	NM_001142929.2		c.1027G>A	p.Val343Met	missense splice_region	Exon 9 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.1381G>A	p.Val461Met	missense splice_region	Exon 9 of 15	ENSP00000337103.2	P28329-1
	CHAT	ENST00000395562.2	TSL:1	c.1135G>A	p.Val379Met	missense splice_region	Exon 10 of 16	ENSP00000378929.2	P28329-2
	CHAT	ENST00000339797.5	TSL:1	c.1027G>A	p.Val343Met	missense splice_region	Exon 9 of 15	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes AF: 0.968 AC: 147239 AN: 152126 Hom.: 71478 Cov.: 32

Gnomad AFR AF: 0.887

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.979

GnomAD2 exomes AF: 0.991 AC: 246545 AN: 248716 AF XY: 0.994

Gnomad AFR exome AF: 0.884

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.996 AC: 1452385 AN: 1457574 Hom.: 723860 Cov.: 32 AF XY: 0.997 AC XY: 722972 AN XY: 725220

African (AFR) AF: 0.882 AC: 29425 AN: 33366

American (AMR) AF: 0.993 AC: 44340 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26086 AN: 26112

East Asian (EAS) AF: 1.00 AC: 39664 AN: 39664

South Asian (SAS) AF: 1.00 AC: 85846 AN: 85864

European-Finnish (FIN) AF: 1.00 AC: 53217 AN: 53218

Middle Eastern (MID) AF: 0.992 AC: 5711 AN: 5758

European-Non Finnish (NFE) AF: 1.00 AC: 1108303 AN: 1108708

Other (OTH) AF: 0.993 AC: 59793 AN: 60228

GnomAD4 genome AF: 0.968 AC: 147345 AN: 152244 Hom.: 71526 Cov.: 32 AF XY: 0.969 AC XY: 72135 AN XY: 74430

African (AFR) AF: 0.887 AC: 36803 AN: 41482

American (AMR) AF: 0.991 AC: 15172 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3463 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68016 AN: 68048

Other (OTH) AF: 0.980 AC: 2069 AN: 2112

Alfa AF: 0.989 Hom.: 196436

Bravo AF: 0.963

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ESP6500AA AF: 0.886 AC: 3905

ESP6500EA AF: 0.999 AC: 8594

ExAC AF: 0.989 AC: 120061

Asia WGS AF: 0.994 AC: 3456 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial infantile myasthenia (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Benign	0.077
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	6.6e-7	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.5	N
PhyloP100		5.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.97	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.048	B
Vest4		0.031
MPC		0.25
ClinPred		0.0036	T
GERP RS		3.9
Varity_R		0.071
gMVP		0.46
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.016
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: rs4838544; hg19: chr10-50856652; COSMIC: COSV107410719; COSMIC: COSV107410719;