dbSNP rs35420992: FGF3:p.Thr136Thr (chr11-69810617-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005247.4(FGF3):c.408G>A(p.Thr136Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.095 in 1,606,998 control chromosomes in the GnomAD database, including 7,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 559 hom., cov: 33)

Exomes 𝑓: 0.097 ( 7367 hom. )

Consequence

FGF3
NM_005247.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.11

Publications

10 publications found

Variant links:

Genes affected

FGF3 (HGNC:3681): (fibroblast growth factor 3) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its similarity with mouse fgf3/int-2, a proto-oncogene activated in virally induced mammary tumors in the mouse. Frequent amplification of this gene has been found in human tumors, which may be important for neoplastic transformation and tumor progression. Studies of the similar genes in mouse and chicken suggested the role in inner ear formation. [provided by RefSeq, Jul 2008]

FGF3 Gene-Disease associations (from GenCC):

deafness with labyrinthine aplasia, microtia, and microdontia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

FGF3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 11-69810617-C-T is Benign according to our data. Variant chr11-69810617-C-T is described in ClinVar as Benign. ClinVar VariationId is 259688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.11 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005247.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF3	NM_005247.4	MANE Select	c.408G>A	p.Thr136Thr	synonymous	Exon 3 of 3	NP_005238.1	P11487

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF3	ENST00000334134.4	TSL:1 MANE Select	c.408G>A	p.Thr136Thr	synonymous	Exon 3 of 3	ENSP00000334122.2	P11487
	FGF3	ENST00000646078.1		n.255G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0776

AC:

11809

AN:

152180

Hom.:

560

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0437

Gnomad AMI

AF:

0.0789

Gnomad AMR

AF:

0.0425

Gnomad ASJ

AF:

0.0374

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.0904

Gnomad FIN

AF:

0.110

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.0722

GnomAD2 exomes

AF:

0.0797

AC:

19721

AN:

247354

AF XY:

0.0821

show subpopulations

Gnomad AFR exome

AF:

0.0443

Gnomad AMR exome

AF:

0.0322

Gnomad ASJ exome

AF:

0.0346

Gnomad EAS exome

AF:

0.00982

Gnomad FIN exome

AF:

0.109

Gnomad NFE exome

AF:

0.106

Gnomad OTH exome

AF:

0.0787

GnomAD4 exome

AF:

0.0969

AC:

140892

AN:

1454700

Hom.:

7367

Cov.:

AF XY:

0.0970

AC XY:

70118

AN XY:

722628

show subpopulations

African (AFR)

AF:

0.0416

AC:

1387

AN:

33302

American (AMR)

AF:

0.0332

AC:

1469

AN:

44290

Ashkenazi Jewish (ASJ)

AF:

0.0376

AC:

977

AN:

25966

East Asian (EAS)

AF:

0.0169

AC:

669

AN:

39518

South Asian (SAS)

AF:

0.0921

AC:

7913

AN:

85892

European-Finnish (FIN)

AF:

0.116

AC:

6073

AN:

52206

Middle Eastern (MID)

AF:

0.0463

AC:

266

AN:

5744

European-Non Finnish (NFE)

AF:

0.106

AC:

117278

AN:

1107762

Other (OTH)

AF:

0.0810

AC:

4860

AN:

60020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

6939

13878

20818

27757

34696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4184

8368

12552

16736

20920

<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:

0.0775

AC:

11806

AN:

152298

Hom.:

559

Cov.:

AF XY:

0.0775

AC XY:

5771

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0436

AC:

1811

AN:

41580

American (AMR)

AF:

0.0425

AC:

650

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0374

AC:

130

AN:

3472

East Asian (EAS)

AF:

0.0160

AC:

AN:

5180

South Asian (SAS)

AF:

0.0909

AC:

439

AN:

4832

European-Finnish (FIN)

AF:

0.110

AC:

1166

AN:

10626

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.107

AC:

7291

AN:

67988

Other (OTH)

AF:

0.0714

AC:

151

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

571

1141

1712

2282

2853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<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:

0.0934

Hom.:

355

Bravo

AF:

0.0692

EpiCase

AF:

0.0949

EpiControl

AF:

0.0932

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.4

(source)

DANN

Benign

0.72

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over