X-78273563-T-C

Variant names:

• chrX-78273563-T-C
• rs1921419237
• NM_006639.4:c.184A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006639.4(CYSLTR1):​c.184A>G​(p.Met62Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,773 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
• Consequence: CYSLTR1 NM_006639.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55

Genes affected

CYSLTR1 (HGNC:17451): (cysteinyl leukotriene receptor 1) This gene encodes a member of the G-protein coupled receptor 1 family. The encoded protein is a receptor for cysteinyl leukotrienes, and is involved in mediating bronchoconstriction via activation of a phosphatidylinositol-calcium second messenger system. Activation of the encoded receptor results in contraction and proliferation of bronchial smooth muscle cells, eosinophil migration, and damage to the mucus layer in the lung. Upregulation of this gene is associated with asthma and dysregulation may also be implicated in cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYSLTR1	NM_006639.4	c.184A>G	p.Met62Val	missense_variant	Exon 3 of 3	ENST00000373304.4	NP_006630.1
CYSLTR1	NM_001282186.2	c.184A>G	p.Met62Val	missense_variant	Exon 2 of 2		NP_001269115.1
CYSLTR1	NM_001282187.2	c.184A>G	p.Met62Val	missense_variant	Exon 4 of 4		NP_001269116.1
CYSLTR1	NM_001282188.2	c.184A>G	p.Met62Val	missense_variant	Exon 4 of 4		NP_001269117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYSLTR1	ENST00000373304.4	c.184A>G	p.Met62Val	missense_variant	Exon 3 of 3	1	NM_006639.4	ENSP00000362401.3
CYSLTR1	ENST00000614798.1	c.184A>G	p.Met62Val	missense_variant	Exon 2 of 2	1		ENSP00000478492.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111773 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33943

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111773 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33943

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000191

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.184A>G (p.M62V) alteration is located in exon 3 (coding exon 1) of the CYSLTR1 gene. This alteration results from a A to G substitution at nucleotide position 184, causing the methionine (M) at amino acid position 62 to be replaced by a valine (V). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	.;T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.021	D;D
Polyphen		0.91	P;P
Vest4		0.31
MutPred		0.50		Loss of stability (P = 0.287);Loss of stability (P = 0.287);
MVP		0.90
MPC		0.042
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.84
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs1921419237; hg19: chrX-77529060;