Genetic Variant NM_005248.3:c.533-8C>G (chr1-27617014-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_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

Publications

6 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGR	NM_005248.3	MANE Select	c.533-8C>G	splice_region intron	N/A	NP_005239.1	P09769
FGR	NM_001042729.2		c.533-8C>G	splice_region intron	N/A	NP_001036194.1	P09769
FGR	NM_001042747.2		c.533-8C>G	splice_region intron	N/A	NP_001036212.1	P09769

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FGR	ENST00000374005.8	TSL:1 MANE Select	c.533-8C>G	splice_region intron	N/A	ENSP00000363117.3	P09769
FGR	ENST00000374004.5	TSL:1	c.533-8C>G	splice_region intron	N/A	ENSP00000363116.1	P09769
FGR	ENST00000968119.1		c.533-8C>G	splice_region intron	N/A	ENSP00000638178.1

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

GnomAD2 exomes

AF:

0.0124

AC:

3109

AN:

251358

AF XY:

0.00993

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 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

African (AFR)

AF:

0.000687

AC:

AN:

33476

American (AMR)

AF:

0.0640

AC:

2864

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00333

AC:

AN:

26136

East Asian (EAS)

AF:

0.0305

AC:

1209

AN:

39700

South Asian (SAS)

AF:

0.00206

AC:

178

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00176

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.000207

AC:

230

AN:

1112002

Other (OTH)

AF:

0.00318

AC:

192

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

286

573

859

1146

1432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.00502

AC:

764

AN:

152314

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

411

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000890

AC:

AN:

41568

American (AMR)

AF:

0.0321

AC:

491

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.0337

AC:

175

AN:

5190

South Asian (SAS)

AF:

0.00207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68014

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000793

Hom.:

Bravo

AF:

0.00886

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.2

(source)

DANN

Benign

0.67

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over