rs773734601

Variant names:

• chrX-78273386-G-A
• rs773734601
• NM_006639.4:c.361C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS2

The NM_006639.4(CYSLTR1):​c.361C>T​(p.Arg121Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,209,248 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000022 (0 hom. 11 hem.)
• Consequence: CYSLTR1 NM_006639.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.58
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• BP6: Variant X-78273386-G-A is Benign according to our data. Variant chrX-78273386-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2660971.
• BS2: High Hemizygotes in GnomAdExome4 at 11 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006639.4. 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
	CYSLTR1	NM_006639.4	MANE Select	c.361C>T	p.Arg121Trp	missense	Exon 3 of 3	NP_006630.1	Q9Y271
	CYSLTR1	NM_001282186.2		c.361C>T	p.Arg121Trp	missense	Exon 2 of 2	NP_001269115.1	Q9Y271
	CYSLTR1	NM_001282187.2		c.361C>T	p.Arg121Trp	missense	Exon 4 of 4	NP_001269116.1	Q9Y271

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYSLTR1	ENST00000373304.4	TSL:1 MANE Select	c.361C>T	p.Arg121Trp	missense	Exon 3 of 3	ENSP00000362401.3	Q9Y271
	CYSLTR1	ENST00000614798.1	TSL:1	c.361C>T	p.Arg121Trp	missense	Exon 2 of 2	ENSP00000478492.1	Q9Y271
	CYSLTR1	ENST00000856868.1		c.361C>T	p.Arg121Trp	missense	Exon 4 of 4	ENSP00000526927.1

Frequencies

GnomAD3 genomes AF: 0.0000539 AC: 6 AN: 111322 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000942

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000328 AC: 6 AN: 182788 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000491

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 24 AN: 1097926 Hom.: 0 Cov.: 33 AF XY: 0.0000303 AC XY: 11 AN XY: 363312

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.0000284 AC: 1 AN: 35154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30197

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000226 AC: 19 AN: 841956

Other (OTH) AF: 0.00 AC: 0 AN: 46084

GnomAD4 genome AF: 0.0000539 AC: 6 AN: 111322 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33556

African (AFR) AF: 0.0000327 AC: 1 AN: 30610

American (AMR) AF: 0.00 AC: 0 AN: 10400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5929

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000942 AC: 5 AN: 53080

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		6.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.82		Gain of catalytic residue at S118 (P = 0.2446)
MVP		1.0
MPC		0.048
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.98
gMVP		0.90
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs773734601; hg19: chrX-77528883; COSMIC: COSV64821437;