Genetic Variant FYN:p.Asp506Glu (chr6-111661835-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 6 hom., cov: 32)

Exomes 𝑓: 0.014 ( 166 hom. )

Consequence

FYN
NM_002037.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.78

Publications

18 publications found

Variant links:

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]

FYN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 10030 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1398 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002037.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FYN	NM_002037.5	MANE Select	c.1518C>G	p.Asp506Glu	missense	Exon 14 of 14	NP_002028.1
FYN	NM_001370529.1		c.1518C>G	p.Asp506Glu	missense	Exon 12 of 12	NP_001357458.1
FYN	NM_153047.4		c.1509C>G	p.Asp503Glu	missense	Exon 14 of 14	NP_694592.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FYN	ENST00000354650.7	TSL:1 MANE Select	c.1518C>G	p.Asp506Glu	missense	Exon 14 of 14	ENSP00000346671.3
FYN	ENST00000229471.8	TSL:1	c.1353C>G	p.Asp451Glu	missense	Exon 11 of 11	ENSP00000229471.4
FYN	ENST00000368667.6	TSL:5	c.1518C>G	p.Asp506Glu	missense	Exon 13 of 13	ENSP00000357656.2

Frequencies

GnomAD3 genomes

AF:

0.00918

AC:

1397

AN:

152182

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00913

AC:

2296

AN:

251466

AF XY:

0.00943

show subpopulations

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 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.:

AF XY:

0.0138

AC XY:

10030

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00284

AC:

AN:

33480

American (AMR)

AF:

0.00762

AC:

341

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00363

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0124

AC:

1072

AN:

86254

European-Finnish (FIN)

AF:

0.00208

AC:

111

AN:

53420

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0161

AC:

17916

AN:

1111992

Other (OTH)

AF:

0.0121

AC:

728

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1085

2169

3254

4338

5423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00918

AC:

1398

AN:

152300

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

618

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00330

AC:

137

AN:

41556

American (AMR)

AF:

0.0103

AC:

157

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1007

AN:

68028

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00963

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0170

AC:

146

ExAC

AF:

0.00906

AC:

1100

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0149

EpiControl

AF:

0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FYN: PP2, BS1, BS2

Oct 22, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.18

Eigen_PC

Benign

0.023

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

PhyloP100

4.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.93

REVEL

Benign

0.090

Sift

Benign

0.30

Sift4G

Benign

0.70

Polyphen

0.0010

Vest4

0.33

MutPred

0.13

Gain of glycosylation at P507 (P = 0.0676)

MVP

0.48

MPC

1.1

ClinPred

0.0065

GERP RS

4.8

Varity_R

0.38

gMVP

0.67

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over