5-39110357-T-G

Variant summary

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

The NM_001465.6(FYB1):c.2434A>C(p.Asn812His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: FYB1 NM_001465.6 missense, splice_region
• Scores: Splicing: ADA: 0.6696
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

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]

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=0.1886135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYB1	NM_001465.6	c.2434A>C	p.Asn812His	missense_variant, splice_region_variant	17/19	ENST00000512982.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYB1	ENST00000512982.4	c.2434A>C	p.Asn812His	missense_variant, splice_region_variant	17/19	2	NM_001465.6	P4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74286

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thrombocytopenia 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 09, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.88	N;N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N;.;.;N;N
REVEL	Benign	0.074
Sift	Benign	0.058	T;.;.;T;D
Sift4G	Benign	0.072	T;.;T;T;T
Polyphen		0.99	D;.;.;D;.
Vest4		0.45
MutPred		0.24		Loss of stability (P = 0.0521);.;.;Loss of stability (P = 0.0521);.;
MVP		0.56
ClinPred		0.51	D
GERP RS		1.1
Varity_R		0.14
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.67
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.090		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: rs1047993806; hg19: chr5-39110459;