Genetic Variant FER:p.Asn261Ser (chr5-108871481-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.15

Variant links:

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]

FER links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023656279).

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FER	NM_005246.4 link	c.782A>G	p.Asn261Ser	missense_variant	Exon 7 of 20	ENST00000281092.9	NP_005237.2	P16591-1W0S0X4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FER	ENST00000281092.9 link	c.782A>G	p.Asn261Ser	missense_variant	Exon 7 of 20	1	NM_005246.4	ENSP00000281092.4	P16591-1
FER	ENST00000504143.6 link	n.*253A>G		non_coding_transcript_exon_variant	Exon 5 of 18	5		ENSP00000421951.2	D6RAF9
FER	ENST00000504143.6 link	n.*253A>G		3_prime_UTR_variant	Exon 5 of 18	5		ENSP00000421951.2	D6RAF9

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

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:

AN:

249074

Hom.:

AF XY:

0.000178

AC XY:

AN XY:

134722

show subpopulations

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.:

Cov.:

AF XY:

0.0000982

AC XY:

AN XY:

723334

show subpopulations

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:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74456

show subpopulations

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.:

Bravo

AF:

0.000234

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.12

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.0060

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.54

REVEL

Benign

0.040

Sift

Benign

0.56

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.22

MVP

0.40

MPC

0.14

ClinPred

0.014

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over