Genetic Variant FCRL3:p.Asn28Asp (chr1-157698600-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_052939.4(FCRL3):c.82A>G(p.Asn28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 1,612,742 control chromosomes in the GnomAD database, including 180,413 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.50 ( 19728 hom., cov: 32)

Exomes 𝑓: 0.47 ( 160685 hom. )

Consequence

FCRL3
NM_052939.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.572

Variant links:

Genes affected

FCRL3 (HGNC:18506): (Fc receptor like 3) This gene encodes a member of the immunoglobulin receptor superfamily and is one of several Fc receptor-like glycoproteins clustered on the long arm of chromosome 1. The encoded protein contains immunoreceptor-tyrosine activation motifs and immunoreceptor-tyrosine inhibitory motifs in its cytoplasmic domain and may play a role in regulation of the immune system. Mutations in this gene have been associated with rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus erythematosus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

FCRL3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.182872E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCRL3	NM_052939.4 link	c.82A>G	p.Asn28Asp	missense_variant	Exon 4 of 15	ENST00000368184.8	NP_443171.2	Q96P31-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FCRL3	ENST00000368184.8 link	c.82A>G	p.Asn28Asp	missense_variant	Exon 4 of 15	1	NM_052939.4	ENSP00000357167.3		Q96P31-1

Frequencies

GnomAD3 genomes

AF:

0.503

AC:

76408

AN:

151948

Hom.:

19697

Cov.:

show subpopulations

Gnomad AFR

AF:

0.628

Gnomad AMI

AF:

0.526

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.489

Gnomad EAS

AF:

0.413

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.432

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.465

Gnomad OTH

AF:

0.497

GnomAD2 exomes

AF:

0.448

AC:

112568

AN:

251050

AF XY:

0.438

show subpopulations

Gnomad AFR exome

AF:

0.633

Gnomad AMR exome

AF:

0.457

Gnomad ASJ exome

AF:

0.473

Gnomad EAS exome

AF:

0.404

Gnomad FIN exome

AF:

0.421

Gnomad NFE exome

AF:

0.465

Gnomad OTH exome

AF:

0.456

GnomAD4 exome

AF:

0.466

AC:

680949

AN:

1460678

Hom.:

160685

Cov.:

AF XY:

0.460

AC XY:

334394

AN XY:

726734

show subpopulations

African (AFR)

AF:

0.633

AC:

21166

AN:

33464

American (AMR)

AF:

0.453

AC:

20248

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.471

AC:

12308

AN:

26130

East Asian (EAS)

AF:

0.404

AC:

16027

AN:

39694

South Asian (SAS)

AF:

0.316

AC:

27291

AN:

86238

European-Finnish (FIN)

AF:

0.429

AC:

22906

AN:

53406

Middle Eastern (MID)

AF:

0.488

AC:

2814

AN:

5768

European-Non Finnish (NFE)

AF:

0.477

AC:

529539

AN:

1110916

Other (OTH)

AF:

0.475

AC:

28650

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

18272

36544

54816

73088

91360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.503

AC:

76482

AN:

152064

Hom.:

19728

Cov.:

AF XY:

0.497

AC XY:

36945

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.628

AC:

26071

AN:

41482

American (AMR)

AF:

0.473

AC:

7236

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.489

AC:

1695

AN:

3468

East Asian (EAS)

AF:

0.412

AC:

2130

AN:

5168

South Asian (SAS)

AF:

0.309

AC:

1491

AN:

4818

European-Finnish (FIN)

AF:

0.432

AC:

4564

AN:

10570

Middle Eastern (MID)

AF:

0.521

AC:

152

AN:

292

European-Non Finnish (NFE)

AF:

0.465

AC:

31611

AN:

67964

Other (OTH)

AF:

0.499

AC:

1054

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1976

3951

5927

7902

9878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.477

Hom.:

82989

Bravo

AF:

0.517

TwinsUK

AF:

0.492

AC:

1824

ALSPAC

AF:

0.475

AC:

1829

ESP6500AA

AF:

0.628

AC:

2767

ESP6500EA

AF:

0.465

AC:

3995

ExAC

AF:

0.450

AC:

54625

Asia WGS

AF:

0.421

AC:

1464

AN:

3478

EpiCase

AF:

0.463

EpiControl

AF:

0.469

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.87

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0080

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0064

.;T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0045

LIST_S2

Benign

0.073

T;T;T

MetaRNN

Benign

0.0000062

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.46

N;N;.

PhyloP100

-0.57

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.95

N;N;.

REVEL

Benign

0.047

Sift

Benign

1.0

T;T;.

Sift4G

Benign

0.72

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.021

MPC

0.0061

ClinPred

0.025

GERP RS

-11

Varity_R

0.043

gMVP

0.056

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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chr1-157698600-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over