5-108871399-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005246.4(FER):c.700A>C(p.Ser234Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FER NM_005246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46

Genes affected

FER (HGNC:3655): (FER tyrosine kinase) The protein encoded by this gene is a member of the FPS/FES family of non-transmembrane receptor tyrosine kinases. It regulates cell-cell adhesion and mediates signaling from the cell surface to the cytoskeleton via growth factor receptors. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome X. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FER	NM_005246.4	c.700A>C	p.Ser234Arg	missense_variant	7/20	ENST00000281092.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FER	ENST00000281092.9	c.700A>C	p.Ser234Arg	missense_variant	7/20	1	NM_005246.4	P1
FER	ENST00000504143.6	c.*171A>C		3_prime_UTR_variant, NMD_transcript_variant	5/18	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.700A>C (p.S234R) alteration is located in exon 7 (coding exon 5) of the FER gene. This alteration results from a A to C substitution at nucleotide position 700, causing the serine (S) at amino acid position 234 to be replaced by an arginine (R). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.36		Gain of solvent accessibility (P = 0.0739);
MVP		0.60
MPC		0.74
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.66
gMVP		0.64

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-108207100;