5-177096596-A-G

Variant names:

• chr5-177096596-A-G
• rs31776
• NM_213647.3:c.2016-8A>G

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.2016-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 1,612,768 control chromosomes in the GnomAD database, including 446,184 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.71 (39349 hom., cov: 31)
  • Exomes 𝑓: 0.74 (406835 hom.)
• Consequence: FGFR4 NM_213647.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001988
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.937
• Publications: 19 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 (BayesDel_noAF=-0.81).
• BP6: Variant 5-177096596-A-G is Benign according to our data. Variant chr5-177096596-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060830.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR4	NM_213647.3	MANE Select	c.2016-8A>G		splice_region intron	N/A	NP_998812.1
	FGFR4	NM_001354984.2		c.2016-8A>G		splice_region intron	N/A	NP_001341913.1
	FGFR4	NM_002011.5		c.2016-8A>G		splice_region intron	N/A	NP_002002.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR4	ENST00000292408.9	TSL:1 MANE Select	c.2016-8A>G		splice_region intron	N/A	ENSP00000292408.4
	FGFR4	ENST00000502906.5	TSL:1	c.2016-8A>G		splice_region intron	N/A	ENSP00000424960.1
	FGFR4	ENST00000393637.5	TSL:1	c.1896-8A>G		splice_region intron	N/A	ENSP00000377254.1

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108604 AN: 151870 Hom.: 39325 Cov.: 31

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.900

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.722

Gnomad OTH AF: 0.704

GnomAD2 exomes AF: 0.771 AC: 193009 AN: 250256 AF XY: 0.774

Gnomad AFR exome AF: 0.619

Gnomad AMR exome AF: 0.844

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.972

Gnomad FIN exome AF: 0.755

Gnomad NFE exome AF: 0.716

Gnomad OTH exome AF: 0.737

GnomAD4 exome AF: 0.743 AC: 1085722 AN: 1460782 Hom.: 406835 Cov.: 56 AF XY: 0.747 AC XY: 542623 AN XY: 726680

African (AFR) AF: 0.622 AC: 20814 AN: 33470

American (AMR) AF: 0.834 AC: 37217 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 18295 AN: 26048

East Asian (EAS) AF: 0.978 AC: 38833 AN: 39700

South Asian (SAS) AF: 0.888 AC: 76530 AN: 86154

European-Finnish (FIN) AF: 0.754 AC: 40210 AN: 53314

Middle Eastern (MID) AF: 0.663 AC: 3821 AN: 5760

European-Non Finnish (NFE) AF: 0.724 AC: 805190 AN: 1111398

Other (OTH) AF: 0.743 AC: 44812 AN: 60334

GnomAD4 genome AF: 0.715 AC: 108667 AN: 151986 Hom.: 39349 Cov.: 31 AF XY: 0.721 AC XY: 53559 AN XY: 74274

African (AFR) AF: 0.626 AC: 25934 AN: 41456

American (AMR) AF: 0.756 AC: 11553 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2467 AN: 3470

East Asian (EAS) AF: 0.975 AC: 5010 AN: 5136

South Asian (SAS) AF: 0.901 AC: 4322 AN: 4796

European-Finnish (FIN) AF: 0.761 AC: 8063 AN: 10600

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.722 AC: 49020 AN: 67934

Other (OTH) AF: 0.702 AC: 1480 AN: 2108

Alfa AF: 0.715 Hom.: 28858

Bravo AF: 0.707

Asia WGS AF: 0.881 AC: 3064 AN: 3478

EpiCase AF: 0.707

EpiControl AF: 0.706

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.57
PhyloP100		-0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.020		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: rs31776; hg19: chr5-176523597; COSMIC: COSV99448720;