5-39122338-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001465.6(FYB1):c.2136G>T(p.Met712Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FYB1 NM_001465.6 missense, splice_region
• Scores: Splicing: ADA: 0.0005416
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0570

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028785348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYB1	NM_001465.6	c.2136G>T	p.Met712Ile	missense_variant, splice_region_variant	14/19	ENST00000512982.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYB1	ENST00000512982.4	c.2136G>T	p.Met712Ile	missense_variant, splice_region_variant	14/19	2	NM_001465.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1402026 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 694708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2023

The c.2136G>T (p.M712I) alteration is located in exon 1 (coding exon 1) of the FYB gene. This alteration results from a G to T substitution at nucleotide position 2136, causing the methionine (M) at amino acid position 712 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.88
DEOGEN2	Benign	0.066	T;.;.;T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.55	N;.;.;N;N
REVEL	Benign	0.045
Sift	Benign	0.41	T;.;.;T;T
Sift4G	Benign	0.57	T;.;T;T;T
Polyphen		0.0010	B;.;.;B;.
Vest4		0.096
MutPred		0.15		Loss of loop (P = 0.0986);.;.;Loss of loop (P = 0.0986);.;
MVP		0.21
ClinPred		0.051	T
GERP RS		0.71
Varity_R		0.080
gMVP		0.033

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00054
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-39122440;