11-62909827-A-G

Position:

• chr11-62909827-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000738.3(CHRM1):​c.1274T>C​(p.Phe425Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRM1 NM_000738.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.21

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]

ENSG00000257002 (HGNC:58194):

LOC124902683 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 11-62909827-A-G is Pathogenic according to our data. Variant chr11-62909827-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1098339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRM1	NM_000738.3	c.1274T>C	p.Phe425Ser	missense_variant	2/2	ENST00000306960.4	NP_000729.2
CHRM1	XM_011544742.3	c.1274T>C	p.Phe425Ser	missense_variant	2/2		XP_011543044.1
LOC124902683	XR_007062700.1	n.86+212A>G		intron_variant
LOC124902683	XR_007062701.1	n.86+212A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRM1	ENST00000306960.4	c.1274T>C	p.Phe425Ser	missense_variant	2/2	1	NM_000738.3	ENSP00000306490.3
CHRM1	ENST00000543973.1	c.1274T>C	p.Phe425Ser	missense_variant	3/3	5		ENSP00000441188.1
ENSG00000257002	ENST00000543624.1	n.70+212A>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting -

CHRM1-related neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Jul 30, 2024

The variant is not observed in the gnomAD v4.0.0 dataset. The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID:34212451). The variant has been observed in at least two similarly affected unrelated individuals (PMID:34212451; 3billion dataset). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.82		Loss of stability (P = 0.0189);Loss of stability (P = 0.0189);
MVP		0.93
MPC		2.2
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.88
gMVP		1.0

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: chr11-62677299;