rs1060505056

Variant names:

• chr5-39138664-CAT-C
• rs1060505056
• NM_001465.6:c.1385_1386delAT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001465.6(FYB1):​c.1385_1386delAT​(p.Tyr462fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000731 in 1,367,934 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: FYB1 NM_001465.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.98
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-39138664-CAT-C is Pathogenic according to our data. Variant chr5-39138664-CAT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 417970.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1385_1386delAT	p.Tyr462fs	frameshift	Exon 6 of 19	NP_001456.3
	FYB1	NM_001243093.2		c.1415_1416delAT	p.Tyr472fs	frameshift	Exon 6 of 19	NP_001230022.1	O15117-3
	FYB1	NM_001349333.2		c.1385_1386delAT	p.Tyr462fs	frameshift	Exon 7 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.1385_1386delAT	p.Tyr462fs	frameshift	Exon 6 of 19	ENSP00000425845.3	O15117-2
	FYB1	ENST00000351578.12	TSL:1	c.1385_1386delAT	p.Tyr462fs	frameshift	Exon 6 of 18	ENSP00000316460.7	O15117-1
	FYB1	ENST00000515010.5	TSL:1	c.1385_1386delAT	p.Tyr462fs	frameshift	Exon 5 of 17	ENSP00000426346.1	O15117-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.31e-7 AC: 1 AN: 1367934 Hom.: 0 AF XY: 0.00000146 AC XY: 1 AN XY: 684042

African (AFR) AF: 0.00 AC: 0 AN: 31160

American (AMR) AF: 0.00 AC: 0 AN: 41438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25080

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38932

South Asian (SAS) AF: 0.00 AC: 0 AN: 80852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1035124

Other (OTH) AF: 0.00 AC: 0 AN: 57066

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Thrombocytopenia 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1060505056; hg19: chr5-39138766;