5-177090796-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_213647.3(FGFR4):c.407C>T(p.Pro136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,613,588 control chromosomes in the GnomAD database, including 481,410 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.75 (42815 hom., cov: 31)
  • Exomes 𝑓: 0.77 (438595 hom.)
• Consequence: FGFR4 NM_213647.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.52

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.291212E-7).
• BP6: Variant 5-177090796-C-T is Benign according to our data. Variant chr5-177090796-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1679938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR4	NM_213647.3	c.407C>T	p.Pro136Leu	missense_variant	4/18	ENST00000292408.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR4	ENST00000292408.9	c.407C>T	p.Pro136Leu	missense_variant	4/18	1	NM_213647.3	P2

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113370 AN: 151876 Hom.: 42756 Cov.: 31

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.893

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.743

GnomAD3 exomes AF: 0.801 AC: 201070 AN: 251148 Hom.: 81471 AF XY: 0.802 AC XY: 108830 AN XY: 135724

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.755

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.885

Gnomad FIN exome AF: 0.813

Gnomad NFE exome AF: 0.751

Gnomad OTH exome AF: 0.778

GnomAD4 exome AF: 0.772 AC: 1128836 AN: 1461594 Hom.: 438595 Cov.: 61 AF XY: 0.774 AC XY: 563070 AN XY: 727102

Gnomad4 AFR exome AF: 0.661

Gnomad4 AMR exome AF: 0.856

Gnomad4 ASJ exome AF: 0.755

Gnomad4 EAS exome AF: 0.999

Gnomad4 SAS exome AF: 0.879

Gnomad4 FIN exome AF: 0.811

Gnomad4 NFE exome AF: 0.755

Gnomad4 OTH exome AF: 0.776

GnomAD4 genome AF: 0.747 AC: 113490 AN: 151994 Hom.: 42815 Cov.: 31 AF XY: 0.753 AC XY: 55975 AN XY: 74310

Gnomad4 AFR AF: 0.661

Gnomad4 AMR AF: 0.788

Gnomad4 ASJ AF: 0.767

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 0.893

Gnomad4 FIN AF: 0.818

Gnomad4 NFE AF: 0.748

Gnomad4 OTH AF: 0.747

Alfa AF: 0.750 Hom.: 108391

Bravo AF: 0.739

TwinsUK AF: 0.752 AC: 2789

ALSPAC AF: 0.771 AC: 2970

ESP6500AA AF: 0.661 AC: 2911

ESP6500EA AF: 0.752 AC: 6467

ExAC AF: 0.795 AC: 96483

Asia WGS AF: 0.926 AC: 3221 AN: 3478

EpiCase AF: 0.733

EpiControl AF: 0.740

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic Hodgkin lymphoma Benign:1

Likely benign, criteria provided, single submitter

research

Pathology Department, Puerta del Mar University Hospital

Oct 01, 2021

- -

FGFR4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	8.0
Dann	Benign	0.32
DEOGEN2	Benign	0.30	T;T;.;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.35	N
MetaRNN	Benign	9.3e-7	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;.;.;N;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.20	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.33	T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.0	B;B;.;B;B
Vest4		0.036
MPC		0.28
ClinPred		0.0033	T
GERP RS		2.9
Varity_R		0.026
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs376618; hg19: chr5-176517797; COSMIC: COSV99448701; COSMIC: COSV99448701;