X-78273725-T-C

Position:

• chrX-78273725-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006639.4(CYSLTR1):​c.22A>G​(p.Thr8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,084,286 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 5 hem.)
• Consequence: CYSLTR1 NM_006639.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21456128).
• BS2: High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYSLTR1	NM_006639.4	c.22A>G	p.Thr8Ala	missense_variant	3/3	ENST00000373304.4	NP_006630.1
CYSLTR1	NM_001282186.2	c.22A>G	p.Thr8Ala	missense_variant	2/2		NP_001269115.1
CYSLTR1	NM_001282187.2	c.22A>G	p.Thr8Ala	missense_variant	4/4		NP_001269116.1
CYSLTR1	NM_001282188.2	c.22A>G	p.Thr8Ala	missense_variant	4/4		NP_001269117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYSLTR1	ENST00000373304.4	c.22A>G	p.Thr8Ala	missense_variant	3/3	1	NM_006639.4	ENSP00000362401.3
CYSLTR1	ENST00000614798.1	c.22A>G	p.Thr8Ala	missense_variant	2/2	1		ENSP00000478492.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000573 AC: 1 AN: 174495 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 60595

Gnomad AFR exome AF: 0.0000769

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 16 AN: 1084286 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 5 AN XY: 352570

Gnomad4 AFR exome AF: 0.0000383

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000334

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000168

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2024

The c.22A>G (p.T8A) 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 22, causing the threonine (T) at amino acid position 8 to be replaced by an alanine (A). 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	0.090
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.20	T;T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.43	.;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.11
Sift	Benign	0.064	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.87	P;P
Vest4		0.18
MutPred		0.23		Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);
MVP		0.86
MPC		0.015
ClinPred		0.089	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.26

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: rs760115491; hg19: chrX-77529222;