NM_004464.4:c.334T>A

Variant names:

• chr4-80267158-T-A
• NM_004464.4:c.334T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004464.4(FGF5):​c.334T>A​(p.Ser112Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGF5 NM_004464.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11233044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGF5	NM_004464.4	c.334T>A	p.Ser112Thr	missense_variant	Exon 1 of 3	ENST00000312465.12	NP_004455.2
FGF5	NM_033143.2	c.334T>A	p.Ser112Thr	missense_variant	Exon 1 of 2		NP_149134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGF5	ENST00000312465.12	c.334T>A	p.Ser112Thr	missense_variant	Exon 1 of 3	1	NM_004464.4	ENSP00000311697.7
FGF5	ENST00000456523.3	c.334T>A	p.Ser112Thr	missense_variant	Exon 1 of 2	1		ENSP00000398353.3
FGF5	ENST00000380628.3	n.334T>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
FGF5	ENST00000507780.1	n.217T>A		non_coding_transcript_exon_variant	Exon 1 of 5	3		ENSP00000423903.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.334T>A (p.S112T) alteration is located in exon 1 (coding exon 1) of the FGF5 gene. This alteration results from a T to A substitution at nucleotide position 334, causing the serine (S) at amino acid position 112 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.10	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.51	N;N
REVEL	Benign	0.24
Sift	Benign	0.85	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.041	B;P
Vest4		0.17
MutPred		0.36		Loss of disorder (P = 0.0573);Loss of disorder (P = 0.0573);
MVP		0.64
MPC		0.076
ClinPred		0.66	D
GERP RS		4.3
Varity_R		0.12
gMVP		0.41

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-81188312;