X-78273008-T-A

Variant names:

• chrX-78273008-T-A
• rs199546618
• NM_006639.4:c.739A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006639.4(CYSLTR1):​c.739A>T​(p.Met247Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,087 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3221299).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYSLTR1	NM_006639.4	c.739A>T	p.Met247Leu	missense_variant	Exon 3 of 3	ENST00000373304.4	NP_006630.1
CYSLTR1	NM_001282186.2	c.739A>T	p.Met247Leu	missense_variant	Exon 2 of 2		NP_001269115.1
CYSLTR1	NM_001282187.2	c.739A>T	p.Met247Leu	missense_variant	Exon 4 of 4		NP_001269116.1
CYSLTR1	NM_001282188.2	c.739A>T	p.Met247Leu	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.739A>T	p.Met247Leu	missense_variant	Exon 3 of 3	1	NM_006639.4	ENSP00000362401.3
CYSLTR1	ENST00000614798.1	c.739A>T	p.Met247Leu	missense_variant	Exon 2 of 2	1		ENSP00000478492.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183179 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67705

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098087 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363477

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.739A>T (p.M247L) alteration is located in exon 3 (coding exon 1) of the CYSLTR1 gene. This alteration results from a A to T substitution at nucleotide position 739, causing the methionine (M) at amino acid position 247 to be replaced by a leucine (L). 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	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.53
DEOGEN2	Benign	0.089	T;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.13	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.70	N;.
REVEL	Benign	0.23
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.82	P;P
Vest4		0.29
MutPred		0.55		Gain of catalytic residue at M247 (P = 0.1514);Gain of catalytic residue at M247 (P = 0.1514);
MVP		0.89
MPC		0.0081
ClinPred		0.17	T
GERP RS		1.4
Varity_R		0.25
gMVP		0.39

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: rs199546618; hg19: chrX-77528505;