Genetic Variant NM_052939.4:c.1643A>C (chr1-157690302-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_052939.4(FCRL3):c.1643A>C(p.Asn548Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N548S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FCRL3
NM_052939.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.68

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FCRL3	NM_052939.4 link	c.1643A>C	p.Asn548Thr	missense_variant	Exon 9 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.1643A>C	p.Asn548Thr	missense_variant	Exon 9 of 15	1	NM_052939.4	ENSP00000357167.3		Q96P31-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251408

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

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:

0.00000274

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.0098

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

4.1

H;H

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.19

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.97

D;D

Vest4

0.80

MutPred

0.74

Gain of relative solvent accessibility (P = 0.0522);Gain of relative solvent accessibility (P = 0.0522);

MVP

0.58

MPC

0.034

ClinPred

0.99

GERP RS

4.5

Varity_R

0.50

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over