chr5-177089952-A-G

Variant names:

• chr5-177089952-A-G
• rs434434
• NM_213647.3:c.91+259A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_213647.3(FGFR4):​c.91+259A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 688,110 control chromosomes in the GnomAD database, including 228,865 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.

• Frequency:
  • Genomes: 𝑓 0.79 (47992 hom., cov: 31)
  • Exomes 𝑓: 0.82 (180873 hom.)
• Consequence: FGFR4 NM_213647.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• 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.91+259A>G		intron	N/A	NP_998812.1	P22455-1
	FGFR4	NM_001354984.2		c.91+259A>G		intron	N/A	NP_001341913.1	P22455-1
	FGFR4	NM_002011.5		c.91+259A>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.91+259A>G		intron	N/A	ENSP00000292408.4	P22455-1
	FGFR4	ENST00000502906.5	TSL:1	c.91+259A>G		intron	N/A	ENSP00000424960.1	P22455-1
	FGFR4	ENST00000393637.5	TSL:1	c.91+259A>G		intron	N/A	ENSP00000377254.1	P22455-2

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120394 AN: 151968 Hom.: 47933 Cov.: 31

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.929

Gnomad FIN AF: 0.849

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.778

GnomAD2 exomes AF: 0.841 AC: 109362 AN: 129990 AF XY: 0.844

Gnomad AFR exome AF: 0.739

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.784

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.780

Gnomad OTH exome AF: 0.806

GnomAD4 exome AF: 0.818 AC: 438676 AN: 536024 Hom.: 180873 Cov.: 4 AF XY: 0.823 AC XY: 238780 AN XY: 290302

African (AFR) AF: 0.753 AC: 11703 AN: 15542

American (AMR) AF: 0.867 AC: 29550 AN: 34068

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 15330 AN: 19606

East Asian (EAS) AF: 1.00 AC: 30582 AN: 30594

South Asian (SAS) AF: 0.915 AC: 56642 AN: 61870

European-Finnish (FIN) AF: 0.843 AC: 26840 AN: 31844

Middle Eastern (MID) AF: 0.742 AC: 2912 AN: 3926

European-Non Finnish (NFE) AF: 0.781 AC: 241210 AN: 308892

Other (OTH) AF: 0.805 AC: 23907 AN: 29682

GnomAD4 genome AF: 0.792 AC: 120512 AN: 152086 Hom.: 47992 Cov.: 31 AF XY: 0.798 AC XY: 59321 AN XY: 74356

African (AFR) AF: 0.751 AC: 31151 AN: 41458

American (AMR) AF: 0.812 AC: 12408 AN: 15278

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

East Asian (EAS) AF: 0.999 AC: 5179 AN: 5184

South Asian (SAS) AF: 0.929 AC: 4479 AN: 4822

European-Finnish (FIN) AF: 0.849 AC: 8997 AN: 10592

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.780 AC: 53024 AN: 67966

Other (OTH) AF: 0.781 AC: 1646 AN: 2108

Alfa AF: 0.783 Hom.: 9766

Bravo AF: 0.785

Asia WGS AF: 0.951 AC: 3308 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	10
DANN	Benign	0.56
PhyloP100		1.1
PromoterAI		0.023	Neutral
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: rs434434; hg19: chr5-176516953; COSMIC: COSV99448683;