Genetic Variant NM_014808.4:c.133C>A (chr2-241373240-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014808.4(FARP2):c.133C>A(p.His45Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H45Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

FARP2
NM_014808.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.42

Publications

0 publications found

Variant links:

Genes affected

FARP2 (HGNC:16460): (FERM, ARH/RhoGEF and pleckstrin domain protein 2) Enables guanyl-nucleotide exchange factor activity. Acts upstream of or within Rac protein signal transduction and neuron remodeling. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

FARP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09363577).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014808.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FARP2	NM_014808.4	MANE Select	c.133C>A	p.His45Asn	missense	Exon 2 of 27	NP_055623.1	O94887-1
FARP2	NM_001282983.2		c.133C>A	p.His45Asn	missense	Exon 2 of 18	NP_001269912.1	O94887-2
FARP2	NM_001282984.2		c.133C>A	p.His45Asn	missense	Exon 2 of 18	NP_001269913.1	O94887-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FARP2	ENST00000264042.8	TSL:1 MANE Select	c.133C>A	p.His45Asn	missense	Exon 2 of 27	ENSP00000264042.3	O94887-1
FARP2	ENST00000373287.8	TSL:1	c.133C>A	p.His45Asn	missense	Exon 2 of 18	ENSP00000362384.4	O94887-2
FARP2	ENST00000903053.1		c.133C>A	p.His45Asn	missense	Exon 2 of 28	ENSP00000573112.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1401290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692492

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31330

American (AMR)

AF:

0.00

AC:

AN:

38310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24522

East Asian (EAS)

AF:

0.00

AC:

AN:

37450

South Asian (SAS)

AF:

0.00

AC:

AN:

79258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5530

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075086

Other (OTH)

AF:

0.0000174

AC:

AN:

57324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.042

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.65

M_CAP

Benign

0.025

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.94

PhyloP100

2.4

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.11

Sift

Benign

0.25

Sift4G

Benign

0.42

Polyphen

0.094

Vest4

0.31

MutPred

0.25

Gain of sheet (P = 0.1208)

MVP

0.73

MPC

0.065

ClinPred

0.089

GERP RS

2.3

PromoterAI

0.038

Neutral

(source)

Varity_R

0.069

gMVP

0.13

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over