11-118894548-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001716.5(CXCR5):c.1004G>A(p.Arg335Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,568,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CXCR5 NM_001716.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

CXCR5 (HGNC:1060): (C-X-C motif chemokine receptor 5) This gene encodes a multi-pass membrane protein that belongs to the CXC chemokine receptor family. It is expressed in mature B-cells and Burkitt's lymphoma. This cytokine receptor binds to B-lymphocyte chemoattractant (BLC), and is involved in B-cell migration into B-cell follicles of spleen and Peyer patches. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

BCL9L (HGNC:23688): (BCL9 like) Enables beta-catenin binding activity. Involved in several processes, including negative regulation of transforming growth factor beta receptor signaling pathway; positive regulation of epithelial to mesenchymal transition; and positive regulation of transcription by RNA polymerase II. Located in nucleolus and nucleoplasm. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061409354).
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CXCR5	NM_001716.5	c.1004G>A	p.Arg335Gln	missense_variant	2/2	ENST00000292174.5
CXCR5	NM_032966.2	c.869G>A	p.Arg290Gln	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CXCR5	ENST00000292174.5	c.1004G>A	p.Arg335Gln	missense_variant	2/2	1	NM_001716.5	P1
BCL9L	ENST00000334801.7	c.*3867C>T		3_prime_UTR_variant	8/8	1		P4

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000145 AC: 31 AN: 213382 Hom.: 0 AF XY: 0.000106 AC XY: 12 AN XY: 112922

Gnomad AFR exome AF: 0.000440

Gnomad AMR exome AF: 0.000190

Gnomad ASJ exome AF: 0.000159

Gnomad EAS exome AF: 0.0000554

Gnomad SAS exome AF: 0.0000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.000389

GnomAD4 exome AF: 0.000111 AC: 157 AN: 1415780 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 76 AN XY: 698132

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000883

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74486

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000157 AC: 19

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

Jun 09, 2022

The c.1004G>A (p.R335Q) alteration is located in exon 2 (coding exon 2) of the CXCR5 gene. This alteration results from a G to A substitution at nucleotide position 1004, causing the arginine (R) at amino acid position 335 to be replaced by a glutamine (Q). 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	0.097
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.0065
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.095	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.052
Sift	Benign	0.27	T
Sift4G	Benign	0.34	T
Polyphen		0.73	P
Vest4		0.093
MVP		0.57
MPC		1.2
ClinPred		0.011	T
GERP RS		3.2
Varity_R		0.082
gMVP		0.40

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: rs140843011; hg19: chr11-118765257;