5-108871481-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005246.4(FER):c.782A>G(p.Asn261Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,606,392 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: FER NM_005246.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023656279).
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FER	NM_005246.4	c.782A>G	p.Asn261Ser	missense_variant	7/20	ENST00000281092.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FER	ENST00000281092.9	c.782A>G	p.Asn261Ser	missense_variant	7/20	1	NM_005246.4	P1
FER	ENST00000504143.6	c.*253A>G		3_prime_UTR_variant, NMD_transcript_variant	5/18	5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000157 AC: 39 AN: 249074 Hom.: 1 AF XY: 0.000178 AC XY: 24 AN XY: 134722

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000765

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000991

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000100 AC: 146 AN: 1454132 Hom.: 1 Cov.: 29 AF XY: 0.0000982 AC XY: 71 AN XY: 723334

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000631

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000942

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000831

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74456

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.0000967 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

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

Mar 25, 2022

The c.782A>G (p.N261S) alteration is located in exon 7 (coding exon 5) of the FER gene. This alteration results from a A to G substitution at nucleotide position 782, causing the asparagine (N) at amino acid position 261 to be replaced by a serine (S). 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	0.060
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	15
Dann	Benign	0.73
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	0.79	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.040
Sift	Benign	0.56	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.22
MVP		0.40
MPC		0.14
ClinPred		0.014	T
GERP RS		3.6
Varity_R		0.028
gMVP		0.12

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: rs182613310; hg19: chr5-108207182;