Genetic Variant FGR:c.533-8C>G (chr1-27617014-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005248.3(FGR):c.533-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,614,098 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 21 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 153 hom. )

Consequence

FGR
NM_005248.3 splice_region, intron

Scores

Splicing: ADA: 0.001693

Clinical Significance

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

Conservation

PhyloP100: -0.140

Variant links:

Genes affected

FGR (HGNC:3697): (FGR proto-oncogene, Src family tyrosine kinase) This gene is a member of the Src family of protein tyrosine kinases (PTKs). The encoded protein contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Infection with Epstein-Barr virus results in the overexpression of this gene. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

FGR links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 1-27617014-G-C is Benign according to our data. Variant chr1-27617014-G-C is described in ClinVar as [Benign]. Clinvar id is 769507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
FGR	NM_005248.3 link	c.533-8C>G	splice_region_variant, intron_variant	Intron 6 of 12	ENST00000374005.8	NP_005239.1	P09769
FGR	NM_001042729.2 link	c.533-8C>G	splice_region_variant, intron_variant	Intron 6 of 12		NP_001036194.1	P09769P78453
FGR	NM_001042747.2 link	c.533-8C>G	splice_region_variant, intron_variant	Intron 6 of 12		NP_001036212.1	P09769

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGR	ENST00000374005.8 link	c.533-8C>G		splice_region_variant, intron_variant	Intron 6 of 12	1	NM_005248.3	ENSP00000363117.3		P09769

Frequencies

GnomAD3 genomes

AF:

0.00504

AC:

767

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0323

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.0336

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.0124

AC:

3109

AN:

251358

Hom.:

113

AF XY:

0.00993

AC XY:

1349

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.0679

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.0299

Gnomad SAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.00962

GnomAD4 exome

AF:

0.00328

AC:

4794

AN:

1461784

Hom.:

153

Cov.:

AF XY:

0.00293

AC XY:

2132

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.0640

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.0305

Gnomad4 SAS exome

AF:

0.00206

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000207

Gnomad4 OTH exome

AF:

0.00318

GnomAD4 genome

AF:

0.00502

AC:

764

AN:

152314

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

411

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.0321

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.0337

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000793

Hom.:

Bravo

AF:

0.00886

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.2

DANN

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0017

dbscSNV1_RF

Benign

0.074

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over