rs351855

Variant names:

• chr5-177093242-G-A
• rs351855
• NM_213647.3:c.1162G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-177093242-G-A
• chr5-177093242-G-C
• chr5-177093242-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_213647.3(FGFR4):​c.1162G>A​(p.Gly388Arg) variant causes a missense change. The variant allele was found at a frequency of 0.303 in 1,612,462 control chromosomes in the GnomAD database, including 76,363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.27 (6207 hom., cov: 33)
  • Exomes 𝑓: 0.31 (70156 hom.)
• Consequence: FGFR4 NM_213647.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:3
• Conservation: PhyloP100: 6.85
• Publications: 363 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=0.0041104257).
• BP6: Variant 5-177093242-G-A is Benign according to our data. Variant chr5-177093242-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 16326.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 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.1162G>A	p.Gly388Arg	missense	Exon 9 of 18	NP_998812.1	P22455-1
	FGFR4	NM_001354984.2		c.1162G>A	p.Gly388Arg	missense	Exon 9 of 18	NP_001341913.1	P22455-1
	FGFR4	NM_002011.5		c.1162G>A	p.Gly388Arg	missense	Exon 9 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.1162G>A	p.Gly388Arg	missense	Exon 9 of 18	ENSP00000292408.4	P22455-1
	FGFR4	ENST00000502906.5	TSL:1	c.1162G>A	p.Gly388Arg	missense	Exon 9 of 18	ENSP00000424960.1	P22455-1
	FGFR4	ENST00000393637.5	TSL:1	c.1058-90G>A		intron	N/A	ENSP00000377254.1	P22455-2

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40763 AN: 151936 Hom.: 6207 Cov.: 33

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.327 AC: 80930 AN: 247408 AF XY: 0.325

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.420

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.306 AC: 447158 AN: 1460408 Hom.: 70156 Cov.: 60 AF XY: 0.307 AC XY: 223241 AN XY: 726378

African (AFR) AF: 0.129 AC: 4302 AN: 33464

American (AMR) AF: 0.407 AC: 18153 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 8238 AN: 26062

East Asian (EAS) AF: 0.437 AC: 17321 AN: 39644

South Asian (SAS) AF: 0.350 AC: 30162 AN: 86186

European-Finnish (FIN) AF: 0.329 AC: 17513 AN: 53196

Middle Eastern (MID) AF: 0.291 AC: 1674 AN: 5756

European-Non Finnish (NFE) AF: 0.298 AC: 331165 AN: 1111168

Other (OTH) AF: 0.309 AC: 18630 AN: 60328

GnomAD4 genome AF: 0.268 AC: 40785 AN: 152054 Hom.: 6207 Cov.: 33 AF XY: 0.272 AC XY: 20216 AN XY: 74304

African (AFR) AF: 0.133 AC: 5519 AN: 41514

American (AMR) AF: 0.330 AC: 5046 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3470

East Asian (EAS) AF: 0.449 AC: 2305 AN: 5134

South Asian (SAS) AF: 0.366 AC: 1765 AN: 4818

European-Finnish (FIN) AF: 0.325 AC: 3441 AN: 10576

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20708 AN: 67940

Other (OTH) AF: 0.272 AC: 574 AN: 2112

Alfa AF: 0.301 Hom.: 22380

Bravo AF: 0.263

TwinsUK AF: 0.297 AC: 1101

ALSPAC AF: 0.291 AC: 1120

ESP6500AA AF: 0.129 AC: 567

ESP6500EA AF: 0.301 AC: 2583

ExAC AF: 0.317 AC: 38447

Asia WGS AF: 0.400 AC: 1386 AN: 3476

EpiCase AF: 0.298

EpiControl AF: 0.301

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	FGFR4-related disorder (2)
-	-	2	not specified (2)
1	-	-	Cancer progression and tumor cell motility (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.5	L
PhyloP100		6.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.16	N
REVEL	Uncertain	0.52
Sift	Benign	0.12	T
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.26		Gain of MoRF binding (P = 0.0102)
MPC		0.83
ClinPred		0.018	T
GERP RS		4.3
BranchPoint Hunter		2.0
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.75
Mutation Taster		=91/9	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: rs351855; hg19: chr5-176520243; COSMIC: COSV52800825; COSMIC: COSV52800825;