rs766332361

Variant names:

• chr5-39118901-C-A
• rs766332361
• NM_001465.6:c.2374G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001465.6(FYB1):​c.2374G>T​(p.Val792Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000391 in 1,536,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: FYB1 NM_001465.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33735675).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYB1	NM_001465.6	MANE Select	c.2374G>T	p.Val792Phe	missense	Exon 16 of 19	NP_001456.3
	FYB1	NM_001243093.2		c.2404G>T	p.Val802Phe	missense	Exon 16 of 19	NP_001230022.1	O15117-3
	FYB1	NM_001349333.2		c.2374G>T	p.Val792Phe	missense	Exon 17 of 20	NP_001336262.1	O15117-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FYB1	ENST00000512982.4	TSL:2 MANE Select	c.2374G>T	p.Val792Phe	missense	Exon 16 of 19	ENSP00000425845.3	O15117-2
	FYB1	ENST00000351578.12	TSL:1	c.2236G>T	p.Val746Phe	missense	Exon 15 of 18	ENSP00000316460.7	O15117-1
	FYB1	ENST00000515010.5	TSL:1	c.2236G>T	p.Val746Phe	missense	Exon 14 of 17	ENSP00000426346.1	O15117-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000181 AC: 4 AN: 220994 AF XY: 0.0000166

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: 0.0000287

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.00000361 AC: 5 AN: 1384182 Hom.: 0 Cov.: 29 AF XY: 0.00000438 AC XY: 3 AN XY: 684356

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

African (AFR) AF: 0.00 AC: 0 AN: 31014

American (AMR) AF: 0.00 AC: 0 AN: 37478

Ashkenazi Jewish (ASJ) AF: 0.0000415 AC: 1 AN: 24100

East Asian (EAS) AF: 0.00 AC: 0 AN: 37518

South Asian (SAS) AF: 0.00 AC: 0 AN: 74186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5470

European-Non Finnish (NFE) AF: 0.00000281 AC: 3 AN: 1066678

Other (OTH) AF: 0.0000177 AC: 1 AN: 56504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000145500), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.89	T
PhyloP100		2.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Benign	0.071	T
Sift4G	Benign	0.15	T
Polyphen		0.52	P
Vest4		0.91
MVP		0.83
ClinPred		0.66	D
GERP RS		6.0
Varity_R		0.27
gMVP		0.38
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs766332361; hg19: chr5-39119003;