Genetic Variant NM_001465.6:c.393G>T (chr5-39202568-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001465.6(FYB1):c.393G>T(p.Trp131Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FYB1
NM_001465.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.639

Publications

2 publications found

Variant links:

Genes affected

FYB1 (HGNC:4036): (FYN binding protein 1) The protein encoded by this gene is an adapter for the FYN protein and LCP2 signaling cascades in T-cells. The encoded protein is involved in platelet activation and controls the expression of interleukin-2. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

FYB1 Gene-Disease associations (from GenCC):

thrombocytopenia 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

FYB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15802649).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001465.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FYB1	NM_001465.6	MANE Select	c.393G>T	p.Trp131Cys	missense	Exon 2 of 19	NP_001456.3
FYB1	NM_001243093.2		c.423G>T	p.Trp141Cys	missense	Exon 2 of 19	NP_001230022.1
FYB1	NM_001349333.2		c.393G>T	p.Trp131Cys	missense	Exon 3 of 20	NP_001336262.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FYB1	ENST00000512982.4	TSL:2 MANE Select	c.393G>T	p.Trp131Cys	missense	Exon 2 of 19	ENSP00000425845.3
FYB1	ENST00000351578.12	TSL:1	c.393G>T	p.Trp131Cys	missense	Exon 2 of 18	ENSP00000316460.7
FYB1	ENST00000515010.5	TSL:1	c.393G>T	p.Trp131Cys	missense	Exon 1 of 17	ENSP00000426346.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249224

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727138

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111868

Other (OTH)

AF:

0.00

AC:

AN:

60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.12

Eigen

Benign

-0.046

Eigen_PC

Benign

-0.082

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.018

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.97

PhyloP100

0.64

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

REVEL

Benign

0.065

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.051

Polyphen

0.76

Vest4

0.29

MutPred

0.14

Loss of glycosylation at T128 (P = 0.1354)

MVP

0.43

ClinPred

0.46

GERP RS

4.4

PromoterAI

-0.0036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.069

Mutation Taster

=96/4

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over