5-177091783-C-T

Variant names:

• chr5-177091783-C-T
• rs452885
• NM_213647.3:c.702C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_213647.3(FGFR4):​c.702C>T​(p.Arg234Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,613,994 control chromosomes in the GnomAD database, including 481,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.75 (42857 hom., cov: 33)
  • Exomes 𝑓: 0.77 (438633 hom.)
• Consequence: FGFR4 NM_213647.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.204
• Publications: 29 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 5-177091783-C-T is Benign according to our data. Variant chr5-177091783-C-T is described in ClinVar as [Benign]. Clinvar id is 3060679.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.204 with no splicing effect.
• 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 rank	MANE	Protein	UniProt
FGFR4	NM_213647.3	c.702C>T	p.Arg234Arg	synonymous_variant	Exon 6 of 18	ENST00000292408.9	NP_998812.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR4	ENST00000292408.9	c.702C>T	p.Arg234Arg	synonymous_variant	Exon 6 of 18	1	NM_213647.3	ENSP00000292408.4

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113479 AN: 152056 Hom.: 42798 Cov.: 33

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.703

Gnomad AMR AF: 0.788

Gnomad ASJ AF: 0.766

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: 0.742

GnomAD2 exomes AF: 0.801 AC: 201253 AN: 251390 AF XY: 0.802

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 FIN exome AF: 0.813

Gnomad NFE exome AF: 0.751

Gnomad OTH exome AF: 0.778

GnomAD4 exome AF: 0.772 AC: 1128966 AN: 1461820 Hom.: 438633 Cov.: 63 AF XY: 0.774 AC XY: 563147 AN XY: 727218

African (AFR) AF: 0.661 AC: 22131 AN: 33476

American (AMR) AF: 0.856 AC: 38283 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 19737 AN: 26130

East Asian (EAS) AF: 0.999 AC: 39673 AN: 39700

South Asian (SAS) AF: 0.879 AC: 75796 AN: 86258

European-Finnish (FIN) AF: 0.811 AC: 43307 AN: 53408

Middle Eastern (MID) AF: 0.691 AC: 3983 AN: 5768

European-Non Finnish (NFE) AF: 0.755 AC: 839172 AN: 1111966

Other (OTH) AF: 0.776 AC: 46884 AN: 60390

GnomAD4 genome AF: 0.747 AC: 113599 AN: 152174 Hom.: 42857 Cov.: 33 AF XY: 0.753 AC XY: 56027 AN XY: 74394

African (AFR) AF: 0.661 AC: 27456 AN: 41514

American (AMR) AF: 0.788 AC: 12060 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2661 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5166 AN: 5174

South Asian (SAS) AF: 0.894 AC: 4311 AN: 4824

European-Finnish (FIN) AF: 0.818 AC: 8665 AN: 10598

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.748 AC: 50866 AN: 67986

Other (OTH) AF: 0.746 AC: 1569 AN: 2104

Alfa AF: 0.750 Hom.: 38214

Bravo AF: 0.739

Asia WGS AF: 0.926 AC: 3222 AN: 3478

EpiCase AF: 0.733

EpiControl AF: 0.740

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

FGFR4-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.51
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs452885; hg19: chr5-176518784; COSMIC: COSV52807660; COSMIC: COSV52807660;