19-32973261-A-T

Variant names:

• chr19-32973261-A-T
• rs780149743
• NM_152266.5:c.65A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152266.5(FAAP24):​c.65A>T​(p.Asn22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: FAAP24 NM_152266.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0150

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28512996).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAAP24	NM_152266.5	c.65A>T	p.Asn22Ile	missense_variant	Exon 2 of 5	ENST00000588258.6	NP_689479.1
FAAP24	XM_005259393.4	c.-7A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5		XP_005259450.1
FAAP24	XM_005259393.4	c.-7A>T		5_prime_UTR_variant	Exon 2 of 5		XP_005259450.1
FAAP24	NM_001300978.2	c.-42-799A>T		intron_variant	Intron 1 of 2		NP_001287907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAAP24	ENST00000588258.6	c.65A>T	p.Asn22Ile	missense_variant	Exon 2 of 5	1	NM_152266.5	ENSP00000466121.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65A>T (p.N22I) alteration is located in exon 2 (coding exon 1) of the FAAP24 gene. This alteration results from a A to T substitution at nucleotide position 65, causing the asparagine (N) at amino acid position 22 to be replaced by an isoleucine (I). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M;M
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.80	P;P
Vest4		0.57
MutPred		0.39		Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);
MVP		0.15
MPC		0.41
ClinPred		0.48	T
GERP RS		-4.7
Varity_R		0.45
gMVP		0.69

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: rs780149743; hg19: chr19-33464167;