Genetic Variant FAAP24:p.Ser126Phe (chr19-32974193-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_152266.5(FAAP24):c.377C>T(p.Ser126Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00594 in 1,613,312 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0048 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0061 ( 50 hom. )

Consequence

FAAP24
NM_152266.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.03

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065547526).

BP6

Variant 19-32974193-C-T is Benign according to our data. Variant chr19-32974193-C-T is described in ClinVar as [Benign]. Clinvar id is 784831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-32974193-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAAP24	NM_152266.5 link	c.377C>T	p.Ser126Phe	missense_variant	Exon 4 of 5	ENST00000588258.6	NP_689479.1	Q9BTP7A0A0S2Z5V6
FAAP24	NM_001300978.2 link	c.92C>T	p.Ser31Phe	missense_variant	Exon 2 of 3		NP_001287907.1	Q9BTP7K7EKQ4
FAAP24	XM_005259393.4 link	c.248C>T	p.Ser83Phe	missense_variant	Exon 4 of 5		XP_005259450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAAP24	ENST00000588258.6 link	c.377C>T	p.Ser126Phe	missense_variant	Exon 4 of 5	1	NM_152266.5	ENSP00000466121.1		Q9BTP7

Frequencies

GnomAD3 genomes

AF:

0.00484

AC:

737

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.0207

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00661

Gnomad OTH

AF:

0.00908

GnomAD3 exomes

AF:

0.00541

AC:

1353

AN:

250188

Hom.:

AF XY:

0.00537

AC XY:

727

AN XY:

135278

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00612

Gnomad ASJ exome

AF:

0.0219

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00201

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00693

Gnomad OTH exome

AF:

0.00868

GnomAD4 exome

AF:

0.00605

AC:

8842

AN:

1460976

Hom.:

Cov.:

AF XY:

0.00606

AC XY:

4405

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.00644

Gnomad4 ASJ exome

AF:

0.0230

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00208

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00643

Gnomad4 OTH exome

AF:

0.00770

GnomAD4 genome

AF:

0.00484

AC:

737

AN:

152336

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

334

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00156

Gnomad4 AMR

AF:

0.00732

Gnomad4 ASJ

AF:

0.0207

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00661

Gnomad4 OTH

AF:

0.00899

Alfa

AF:

0.00713

Hom.:

Bravo

AF:

0.00552

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00651

AC:

ExAC

AF:

0.00502

AC:

609

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00954

EpiControl

AF:

0.00895

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FAAP24-related disorder

Benign:1

Feb 24, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;T;.;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.86

.;.;D;D

MetaRNN

Benign

0.0066

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

.;M;.;M

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.90

.;P;.;P

Vest4

0.75

MVP

0.36

MPC

0.77

ClinPred

0.032

GERP RS

4.5

Varity_R

0.53

gMVP

0.76

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