6-111661835-G-C

Position:

• chr6-111661835-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002037.5(FYN):​c.1518C>G​(p.Asp506Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0135 in 1,614,168 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0092 (6 hom., cov: 32)
  • Exomes 𝑓: 0.014 (166 hom.)
• Consequence: FYN NM_002037.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.78

Genes affected

FYN (HGNC:4037): (FYN proto-oncogene, Src family tyrosine kinase) This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FYN
• BP4: Computational evidence support a benign effect (MetaRNN=0.008390069).
• BP6: Variant 6-111661835-G-C is Benign according to our data. Variant chr6-111661835-G-C is described in ClinVar as [Benign]. Clinvar id is 789183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0139 (20391/1461868) while in subpopulation NFE AF= 0.0161 (17916/1111992). AF 95% confidence interval is 0.0159. There are 166 homozygotes in gnomad4_exome. There are 10030 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1398 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FYN	NM_002037.5	c.1518C>G	p.Asp506Glu	missense_variant	14/14	ENST00000354650.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FYN	ENST00000354650.7	c.1518C>G	p.Asp506Glu	missense_variant	14/14	1	NM_002037.5	P3

Frequencies

GnomAD3 genomes AF: 0.00918 AC: 1397 AN: 152182 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00913 AC: 2296 AN: 251466 Hom.: 25 AF XY: 0.00943 AC XY: 1282 AN XY: 135914

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00743

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0139 AC: 20391 AN: 1461868 Hom.: 166 Cov.: 31 AF XY: 0.0138 AC XY: 10030 AN XY: 727236

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.00762

Gnomad4 ASJ exome AF: 0.00363

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.00208

Gnomad4 NFE exome AF: 0.0161

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00918 AC: 1398 AN: 152300 Hom.: 6 Cov.: 32 AF XY: 0.00830 AC XY: 618 AN XY: 74476

Gnomad4 AFR AF: 0.00330

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.0110 Hom.: 10

Bravo AF: 0.00963

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.00906 AC: 1100

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0149

EpiControl AF: 0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	FYN: PP2, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.18
Eigen_PC	Benign	0.023
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;.;.;T;T;.
MetaRNN	Benign	0.0084	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.93	N;N;N;N;N;N
REVEL	Benign	0.090
Sift	Benign	0.30	T;T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;.;B;B;B;.
Vest4		0.33
MutPred		0.13		.;.;Gain of glycosylation at P507 (P = 0.0676);.;Gain of glycosylation at P507 (P = 0.0676);.;
MVP		0.48
MPC		1.1
ClinPred		0.0065	T
GERP RS		4.8
Varity_R		0.38
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs28763975; hg19: chr6-111983038; COSMIC: COSV57616118;