Genetic Variant NM_006639.4:c.65G>A (chrX-78273682-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006639.4(CYSLTR1):c.65G>A(p.Arg22His) variant causes a missense change. The variant allele was found at a frequency of 0.000048 in 1,208,546 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000050 ( 0 hom. 21 hem. )

Consequence

CYSLTR1
NM_006639.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.88

Variant links:

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]

CYSLTR1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYSLTR1	NM_006639.4 link	c.65G>A	p.Arg22His	missense_variant	Exon 3 of 3	ENST00000373304.4	NP_006630.1	Q9Y271Q38Q91Q38Q88
CYSLTR1	NM_001282186.2 link	c.65G>A	p.Arg22His	missense_variant	Exon 2 of 2		NP_001269115.1	Q9Y271Q38Q91Q38Q88
CYSLTR1	NM_001282187.2 link	c.65G>A	p.Arg22His	missense_variant	Exon 4 of 4		NP_001269116.1	Q9Y271Q38Q91Q38Q88
CYSLTR1	NM_001282188.2 link	c.65G>A	p.Arg22His	missense_variant	Exon 4 of 4		NP_001269117.1	Q9Y271Q38Q91Q38Q88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYSLTR1	ENST00000373304.4 link	c.65G>A	p.Arg22His	missense_variant	Exon 3 of 3	1	NM_006639.4	ENSP00000362401.3		Q9Y271
CYSLTR1	ENST00000614798.1 link	c.65G>A	p.Arg22His	missense_variant	Exon 2 of 2	1		ENSP00000478492.1		Q9Y271

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111860

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34058

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000498

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000603

AC:

AN:

182292

Hom.:

AF XY:

0.0000448

AC XY:

AN XY:

66954

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000723

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000438

Gnomad NFE exome

AF:

0.0000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000502

AC:

AN:

1096686

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

362116

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.000420

Gnomad4 NFE exome

AF:

0.0000321

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111860

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34058

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000498

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65G>A (p.R22H) alteration is located in exon 3 (coding exon 1) of the CYSLTR1 gene. This alteration results from a G to A substitution at nucleotide position 65, causing the arginine (R) at amino acid position 22 to be replaced by a histidine (H). 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

Pathogenic

0.82

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

D;D

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.8

D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.031

D;D

Polyphen

1.0

D;D

Vest4

0.59

MutPred

0.47

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.83

MPC

0.044

ClinPred

0.47

GERP RS

4.5

Varity_R

0.59

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over