Genetic Variant FGFR4:p.Ser137Ser (chr5-177090800-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_213647.3(FGFR4):c.411G>A(p.Ser137Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,614,022 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0042 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0070 ( 49 hom. )

Consequence

FGFR4
NM_213647.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.78

Publications

1 publications found

Variant links:

Genes affected

FGFR4 (HGNC:3691): (fibroblast growth factor receptor 4) The protein encoded by this gene is a tyrosine kinase and cell surface receptor for fibroblast growth factors. The encoded protein is involved in the regulation of several pathways, including cell proliferation, cell differentiation, cell migration, lipid metabolism, bile acid biosynthesis, vitamin D metabolism, glucose uptake, and phosphate homeostasis. This protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. [provided by RefSeq, Aug 2017]

FGFR4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.008).

BP6

Variant 5-177090800-G-A is Benign according to our data. Variant chr5-177090800-G-A is described in ClinVar as [Benign]. Clinvar id is 773176.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.78 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 49 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR4	NM_213647.3 link	c.411G>A	p.Ser137Ser	synonymous_variant	Exon 4 of 18	ENST00000292408.9	NP_998812.1	P22455-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR4	ENST00000292408.9 link	c.411G>A	p.Ser137Ser	synonymous_variant	Exon 4 of 18	1	NM_213647.3	ENSP00000292408.4		P22455-1

Frequencies

GnomAD3 genomes

AF:

0.00424

AC:

645

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00740

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00416

AC:

1046

AN:

251274

AF XY:

0.00409

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00365

Gnomad NFE exome

AF:

0.00695

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00700

AC:

10228

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00679

AC XY:

4935

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.000956

AC:

AN:

33480

American (AMR)

AF:

0.00141

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00177

AC:

153

AN:

86246

European-Finnish (FIN)

AF:

0.00358

AC:

191

AN:

53412

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00840

AC:

9345

AN:

1111928

Other (OTH)

AF:

0.00611

AC:

369

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

531

1063

1594

2126

2657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00424

AC:

645

AN:

152262

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

305

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41558

American (AMR)

AF:

0.00177

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00740

AC:

503

AN:

67998

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00658

Hom.:

Bravo

AF:

0.00409

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00747

EpiControl

AF:

0.00622

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.15

(source)

DANN

Benign

0.45

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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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5-177090800-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over