11-62909990-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000738.3(CHRM1):c.1111C>T(p.Leu371Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRM1 NM_000738.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

Genes affected

CHRM1 (HGNC:1950): (cholinergic receptor muscarinic 1) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 1 is involved in mediation of vagally-induced bronchoconstriction and in the acid secretion of the gastrointestinal tract. The gene encoding this receptor is localized to 11q13. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHRM1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRM1	NM_000738.3	c.1111C>T	p.Leu371Phe	missense_variant	2/2	ENST00000306960.4
LOC124902683	XR_007062701.1	n.86+375G>A		intron_variant, non_coding_transcript_variant
CHRM1	XM_011544742.3	c.1111C>T	p.Leu371Phe	missense_variant	2/2
LOC124902683	XR_007062700.1	n.86+375G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRM1	ENST00000306960.4	c.1111C>T	p.Leu371Phe	missense_variant	2/2	1	NM_000738.3	P1
	ENST00000543624.1	n.70+375G>A		intron_variant, non_coding_transcript_variant		3
CHRM1	ENST00000543973.1	c.1111C>T	p.Leu371Phe	missense_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.1111C>T (p.L371F) alteration is located in exon 2 (coding exon 1) of the CHRM1 gene. This alteration results from a C to T substitution at nucleotide position 1111, causing the leucine (L) at amino acid position 371 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	0.99	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.63		Loss of stability (P = 0.0853);Loss of stability (P = 0.0853);
MVP		0.80
MPC		2.1
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.67
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-62677462; COSMIC: COSV100186257; COSMIC: COSV100186257;