5-108883422-T-C

Variant summary

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

The NM_005246.4(FER):c.950T>C(p.Met317Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FER NM_005246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08400139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FER	NM_005246.4	c.950T>C	p.Met317Thr	missense_variant	9/20	ENST00000281092.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FER	ENST00000281092.9	c.950T>C	p.Met317Thr	missense_variant	9/20	1	NM_005246.4	P1
FER	ENST00000504143.6	c.*421T>C		3_prime_UTR_variant, NMD_transcript_variant	7/18	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455856 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 13, 2024

The c.950T>C (p.M317T) alteration is located in exon 9 (coding exon 7) of the FER gene. This alteration results from a T to C substitution at nucleotide position 950, causing the methionine (M) at amino acid position 317 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	0.072
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	15
Dann	Benign	0.79
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.050	N
MutationTaster	Benign	0.99	D;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.070
Sift	Benign	0.52	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.26		Loss of catalytic residue at M317 (P = 0.0335);
MVP		0.31
MPC		0.20
ClinPred		0.095	T
GERP RS		4.3
Varity_R		0.044
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs1454761319; hg19: chr5-108219123;