Genetic Variant FAAP24:p.Arg95Gln (chr19-32974100-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_152266.5(FAAP24):c.284G>A(p.Arg95Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000541 in 1,614,094 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

FAAP24
NM_152266.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.607

Variant links:

Genes affected

FAAP24 (HGNC:28467): (FA core complex associated protein 24) FAAP24 is a component of the Fanconi anemia (FA) core complex (see MIM 227650), which plays a crucial role in DNA damage response (Ciccia et al., 2007 [PubMed 17289582]).[supplied by OMIM, Mar 2008]

FAAP24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043139756).

BP6

Variant 19-32974100-G-A is Benign according to our data. Variant chr19-32974100-G-A is described in ClinVar as [Benign]. Clinvar id is 714784.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAAP24	NM_152266.5 link	c.284G>A	p.Arg95Gln	missense_variant	Exon 4 of 5	ENST00000588258.6	NP_689479.1	Q9BTP7A0A0S2Z5V6
FAAP24	XM_005259393.4 link	c.155G>A	p.Arg52Gln	missense_variant	Exon 4 of 5		XP_005259450.1
FAAP24	NM_001300978.2 link	c.-2G>A		5_prime_UTR_variant	Exon 2 of 3		NP_001287907.1	Q9BTP7K7EKQ4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAAP24	ENST00000588258.6 link	c.284G>A	p.Arg95Gln	missense_variant	Exon 4 of 5	1	NM_152266.5	ENSP00000466121.1		Q9BTP7

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

469

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000835

AC:

210

AN:

251384

Hom.:

AF XY:

0.000640

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000276

AC:

404

AN:

1461842

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00938

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.00309

AC:

470

AN:

152252

Hom.:

Cov.:

AF XY:

0.00275

AC XY:

205

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0100

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.00312

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00105

AC:

127

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FAAP24-related disorder

Benign:1

Jul 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.6

DANN

Benign

0.90

DEOGEN2

Benign

0.0081

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.49

.;T

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

N;N

Sift4G

Benign

0.69

T;T

Polyphen

0.0

B;B

Vest4

0.11

MVP

0.055

MPC

0.33

ClinPred

0.00082

GERP RS

-1.4

Varity_R

0.087

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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