rs368204813

Variant names:

• chr4-80286341-A-G
• rs368204813
• ENST00000456523.3:c.372A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-80286341-A-G
• chr4-80286341-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_033143.2(FGF5):​c.372A>G​(p.Ter124Trpext*?) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FGF5 NM_033143.2 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_033143.2 Downstream stopcodon found after 202 codons.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033143.2. 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
	FGF5	NM_004464.4	MANE Select	c.476A>G	p.Asp159Gly	missense	Exon 3 of 3	NP_004455.2	P12034-1
	FGF5	NM_033143.2		c.372A>G	p.Ter124Trpext*?	stop_lost	Exon 2 of 2	NP_149134.1	Q8NBG6
	FGF5	NM_001291812.2		c.47A>G	p.Asp16Gly	missense	Exon 3 of 3	NP_001278741.1	Q8NBG6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGF5	ENST00000456523.3	TSL:1	c.372A>G	p.Ter124Trpext*?	stop_lost	Exon 2 of 2	ENSP00000398353.3	P12034-2
	FGF5	ENST00000312465.12	TSL:1 MANE Select	c.476A>G	p.Asp159Gly	missense	Exon 3 of 3	ENSP00000311697.7	P12034-1
	FGF5	ENST00000503413.1	TSL:2	n.425A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438328 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 712798

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32206

American (AMR) AF: 0.00 AC: 0 AN: 40810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 83750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099448

Other (OTH) AF: 0.00 AC: 0 AN: 59186

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Benign	0.86
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.90	T
PhyloP100		9.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		0.97	D
Vest4		0.60
MutPred		0.65		Gain of MoRF binding (P = 0.0354)
MVP		0.83
MPC		0.48
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.61
Mutation Taster		=24/176	disease causing

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: rs368204813; hg19: chr4-81207495;