4-80286809-A-G

Variant names:

• chr4-80286809-A-G
• rs3733336
• NM_004464.4:c.*137A>G

Variant summary

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

The NM_004464.4(FGF5):​c.*137A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 657,840 control chromosomes in the GnomAD database, including 38,008 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 0.34 (8838 hom., cov: 32)
  • Exomes 𝑓: 0.34 (29170 hom.)
• Consequence: FGF5 NM_004464.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126
• Publications: 30 publications found

Genes affected

FGF5 (HGNC:3683): (fibroblast growth factor 5) The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities, and are involved in a variety of biological processes, including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified as an oncogene, which confers transforming potential when transfected into mammalian cells. Targeted disruption of the homolog of this gene in mouse resulted in the phenotype of abnormally long hair, which suggested a function as an inhibitor of hair elongation. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

FGF5 Gene-Disease associations (from GenCC):

• familial isolated trichomegaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• trichomegaly

  Inheritance: AR Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF5	NM_004464.4	c.*137A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000312465.12	NP_004455.2
FGF5	NM_001291812.2	c.*137A>G		3_prime_UTR_variant	Exon 3 of 3		NP_001278741.1
FGF5	NM_033143.2	c.*468A>G		3_prime_UTR_variant	Exon 2 of 2		NP_149134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF5	ENST00000312465.12	c.*137A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_004464.4	ENSP00000311697.7
FGF5	ENST00000456523.3	c.*468A>G		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000398353.3
FGF5	ENST00000503413.1	n.893A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
FGF5	ENST00000507780.1	n.342+11797A>G		intron_variant	Intron 2 of 4	3		ENSP00000423903.1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51531 AN: 151930 Hom.: 8835 Cov.: 32

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.325

GnomAD4 exome AF: 0.336 AC: 169947 AN: 505792 Hom.: 29170 Cov.: 6 AF XY: 0.332 AC XY: 87367 AN XY: 263438

African (AFR) AF: 0.330 AC: 4441 AN: 13456

American (AMR) AF: 0.362 AC: 6849 AN: 18922

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 3836 AN: 14000

East Asian (EAS) AF: 0.210 AC: 6618 AN: 31542

South Asian (SAS) AF: 0.261 AC: 11219 AN: 43036

European-Finnish (FIN) AF: 0.362 AC: 11184 AN: 30914

Middle Eastern (MID) AF: 0.254 AC: 789 AN: 3112

European-Non Finnish (NFE) AF: 0.358 AC: 115491 AN: 322840

Other (OTH) AF: 0.340 AC: 9520 AN: 27970

GnomAD4 genome AF: 0.339 AC: 51544 AN: 152048 Hom.: 8838 Cov.: 32 AF XY: 0.336 AC XY: 24971 AN XY: 74320

African (AFR) AF: 0.332 AC: 13770 AN: 41496

American (AMR) AF: 0.361 AC: 5502 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3470

East Asian (EAS) AF: 0.241 AC: 1247 AN: 5170

South Asian (SAS) AF: 0.251 AC: 1207 AN: 4816

European-Finnish (FIN) AF: 0.337 AC: 3561 AN: 10576

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24089 AN: 67952

Other (OTH) AF: 0.320 AC: 676 AN: 2110

Alfa AF: 0.348 Hom.: 16111

Bravo AF: 0.343

Asia WGS AF: 0.270 AC: 940 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.6
DANN	Benign	0.68
PhyloP100		0.13
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: rs3733336; hg19: chr4-81207963;