X-78273682-C-A

Variant names:

• chrX-78273682-C-A
• NM_006639.4:c.65G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006639.4(CYSLTR1):​c.65G>T​(p.Arg22Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,096,686 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: CYSLTR1 NM_006639.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYSLTR1	NM_006639.4	c.65G>T	p.Arg22Leu	missense_variant	Exon 3 of 3	ENST00000373304.4	NP_006630.1
CYSLTR1	NM_001282186.2	c.65G>T	p.Arg22Leu	missense_variant	Exon 2 of 2		NP_001269115.1
CYSLTR1	NM_001282187.2	c.65G>T	p.Arg22Leu	missense_variant	Exon 4 of 4		NP_001269116.1
CYSLTR1	NM_001282188.2	c.65G>T	p.Arg22Leu	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.65G>T	p.Arg22Leu	missense_variant	Exon 3 of 3	1	NM_006639.4	ENSP00000362401.3
CYSLTR1	ENST00000614798.1	c.65G>T	p.Arg22Leu	missense_variant	Exon 2 of 2	1		ENSP00000478492.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096686 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 362116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.3	D;.
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;.
Sift4G	Benign	0.072	T;T
Polyphen		1.0	D;D
Vest4		0.74
MutPred		0.48		Loss of catalytic residue at R22 (P = 0.2054);Loss of catalytic residue at R22 (P = 0.2054);
MVP		0.91
MPC		0.043
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.73
gMVP		0.58

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: chrX-77529179; COSMIC: COSV64820315;