NM_213647.3:c.535A>G

Variant names:

• chr5-177091036-A-G
• rs55675160
• NM_213647.3:c.535A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_213647.3(FGFR4):​c.535A>G​(p.Thr179Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,610,462 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: FGFR4 NM_213647.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.70
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007867873).
• BP6: Variant 5-177091036-A-G is Benign according to our data. Variant chr5-177091036-A-G is described in ClinVar as Benign. ClinVar VariationId is 3048070.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00121 (184/152228) while in subpopulation EAS AF = 0.0324 (168/5178). AF 95% confidence interval is 0.0284. There are 4 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 gene

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.535A>G	p.Thr179Ala	missense	Exon 5 of 18	NP_998812.1	P22455-1
	FGFR4	NM_001354984.2		c.535A>G	p.Thr179Ala	missense	Exon 5 of 18	NP_001341913.1	P22455-1
	FGFR4	NM_002011.5		c.535A>G	p.Thr179Ala	missense	Exon 5 of 18	NP_002002.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR4	ENST00000292408.9	TSL:1 MANE Select	c.535A>G	p.Thr179Ala	missense	Exon 5 of 18	ENSP00000292408.4	P22455-1
	FGFR4	ENST00000502906.5	TSL:1	c.535A>G	p.Thr179Ala	missense	Exon 5 of 18	ENSP00000424960.1	P22455-1
	FGFR4	ENST00000393637.5	TSL:1	c.535A>G	p.Thr179Ala	missense	Exon 4 of 16	ENSP00000377254.1	P22455-2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152110 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0326

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00275 AC: 690 AN: 250730 AF XY: 0.00261

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0354

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00106 AC: 1541 AN: 1458234 Hom.: 18 Cov.: 33 AF XY: 0.00105 AC XY: 760 AN XY: 724546

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.0000672 AC: 3 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26120

East Asian (EAS) AF: 0.0306 AC: 1209 AN: 39540

South Asian (SAS) AF: 0.000592 AC: 51 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5758

European-Non Finnish (NFE) AF: 0.000179 AC: 198 AN: 1108982

Other (OTH) AF: 0.00123 AC: 74 AN: 60200

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152228 Hom.: 4 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74430

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0324 AC: 168 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.00169

ExAC AF: 0.00269 AC: 327

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	FGFR4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.8
DANN	Benign	0.83
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.99	L
PhyloP100		1.7
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.28	T
Sift4G	Benign	0.68	T
Polyphen		0.059	B
Vest4		0.16
MVP		0.74
MPC		0.29
ClinPred		0.0076	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.23
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55675160; hg19: chr5-176518037; COSMIC: COSV52801175; COSMIC: COSV52801175;