19-32974208-A-C

Variant names:

• chr19-32974208-A-C
• rs1352538271
• NM_152266.5:c.392A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152266.5(FAAP24):​c.392A>C​(p.Gln131Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAAP24 NM_152266.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.48

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAAP24	NM_152266.5	c.392A>C	p.Gln131Pro	missense_variant	Exon 4 of 5	ENST00000588258.6	NP_689479.1
FAAP24	NM_001300978.2	c.107A>C	p.Gln36Pro	missense_variant	Exon 2 of 3		NP_001287907.1
FAAP24	XM_005259393.4	c.263A>C	p.Gln88Pro	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	c.392A>C	p.Gln131Pro	missense_variant	Exon 4 of 5	1	NM_152266.5	ENSP00000466121.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460588 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.392A>C (p.Q131P) alteration is located in exon 4 (coding exon 3) of the FAAP24 gene. This alteration results from a A to C substitution at nucleotide position 392, causing the glutamine (Q) at amino acid position 131 to be replaced by a proline (P). 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	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	.;.;T;T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.6	.;M;.;M
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.96	.;P;.;P
Vest4		0.85
MutPred		0.45		.;Gain of disorder (P = 0.1828);.;Gain of disorder (P = 0.1828);
MVP		0.30
MPC		0.58
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.93
gMVP		0.84

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: rs1352538271; hg19: chr19-33465114;