1-157521265-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031281.3(FCRL5):c.2267T>G(p.Leu756Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FCRL5 NM_031281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

Genes affected

FCRL5 (HGNC:18508): (Fc receptor like 5) This gene encodes a member of the immunoglobulin receptor superfamily and the Fc-receptor like family. This gene and several other Fc receptor-like gene members are clustered on the long arm of chromosome 1. The encoded protein is a single-pass type I membrane protein and contains 8 immunoglobulin-like C2-type domains. This gene is implicated in B cell development and lymphomagenesis. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20808575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCRL5	NM_031281.3	c.2267T>G	p.Leu756Arg	missense_variant	11/17	ENST00000361835.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCRL5	ENST00000361835.8	c.2267T>G	p.Leu756Arg	missense_variant	11/17	1	NM_031281.3	P1
FCRL5	ENST00000461387.5	n.1530T>G		non_coding_transcript_exon_variant	1/7	2
FCRL5	ENST00000497286.5	n.1360T>G		non_coding_transcript_exon_variant	3/9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461350 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726988

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

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

Apr 07, 2022

The c.2267T>G (p.L756R) alteration is located in exon 11 (coding exon 11) of the FCRL5 gene. This alteration results from a T to G substitution at nucleotide position 2267, causing the leucine (L) at amino acid position 756 to be replaced by an arginine (R). 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	0.18
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.0099
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.078	B
Vest4		0.42
MutPred		0.60		Gain of disorder (P = 0.0202);
MVP		0.18
MPC		0.48
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.66
gMVP		0.38

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: rs1650177955; hg19: chr1-157491055;