5-177090291-A-G

Variant names:

• chr5-177090291-A-G
• rs442856
• NM_213647.3:c.92-99A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_213647.3(FGFR4):​c.92-99A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,566,204 control chromosomes in the GnomAD database, including 505,568 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.79 (47991 hom., cov: 33)
  • Exomes 𝑓: 0.80 (457577 hom.)
• Consequence: FGFR4 NM_213647.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.719
• Publications: 15 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 -10 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (REVEL=0.038).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213647.3. 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
	FGFR4	NM_213647.3	MANE Select	c.92-99A>G		intron	N/A	NP_998812.1	P22455-1
	FGFR4	NM_001354984.2		c.92-99A>G		intron	N/A	NP_001341913.1	P22455-1
	FGFR4	NM_002011.5		c.92-99A>G		intron	N/A	NP_002002.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR4	ENST00000292408.9	TSL:1 MANE Select	c.92-99A>G		intron	N/A	ENSP00000292408.4	P22455-1
	FGFR4	ENST00000502906.5	TSL:1	c.92-99A>G		intron	N/A	ENSP00000424960.1	P22455-1
	FGFR4	ENST00000393637.5	TSL:1	c.92-99A>G		intron	N/A	ENSP00000377254.1	P22455-2

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120405 AN: 152022 Hom.: 47932 Cov.: 33

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.929

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.742

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.778

GnomAD2 exomes AF: 0.833 AC: 188883 AN: 226708 AF XY: 0.833

Gnomad AFR exome AF: 0.748

Gnomad AMR exome AF: 0.879

Gnomad ASJ exome AF: 0.782

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.845

Gnomad NFE exome AF: 0.781

Gnomad OTH exome AF: 0.805

GnomAD4 exome AF: 0.802 AC: 1134742 AN: 1414064 Hom.: 457577 Cov.: 25 AF XY: 0.805 AC XY: 567797 AN XY: 705606

African (AFR) AF: 0.753 AC: 24772 AN: 32904

American (AMR) AF: 0.872 AC: 38739 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20230 AN: 25884

East Asian (EAS) AF: 1.00 AC: 39491 AN: 39510

South Asian (SAS) AF: 0.916 AC: 77541 AN: 84692

European-Finnish (FIN) AF: 0.843 AC: 32230 AN: 38254

Middle Eastern (MID) AF: 0.743 AC: 4234 AN: 5698

European-Non Finnish (NFE) AF: 0.784 AC: 849791 AN: 1083600

Other (OTH) AF: 0.807 AC: 47714 AN: 59106

GnomAD4 genome AF: 0.792 AC: 120523 AN: 152140 Hom.: 47991 Cov.: 33 AF XY: 0.797 AC XY: 59309 AN XY: 74376

African (AFR) AF: 0.751 AC: 31155 AN: 41476

American (AMR) AF: 0.812 AC: 12414 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.790 AC: 2742 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5169 AN: 5174

South Asian (SAS) AF: 0.929 AC: 4487 AN: 4830

European-Finnish (FIN) AF: 0.849 AC: 8998 AN: 10602

Middle Eastern (MID) AF: 0.740 AC: 216 AN: 292

European-Non Finnish (NFE) AF: 0.780 AC: 53021 AN: 67972

Other (OTH) AF: 0.781 AC: 1651 AN: 2114

Alfa AF: 0.792 Hom.: 33397

Bravo AF: 0.785

Asia WGS AF: 0.951 AC: 3308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.41
PhyloP100		-0.72
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs442856; hg19: chr5-176517292; COSMIC: COSV99448692;