19-32974193-C-A

Variant names:

• chr19-32974193-C-A
• rs36017455
• NM_152266.5:c.377C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152266.5(FAAP24):​c.377C>A​(p.Ser126Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S126F) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAAP24 NM_152266.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.03
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• lymphoproliferative syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152266.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAAP24	NM_152266.5	MANE Select	c.377C>A	p.Ser126Tyr	missense	Exon 4 of 5	NP_689479.1	Q9BTP7
	FAAP24	NM_001300978.2		c.92C>A	p.Ser31Tyr	missense	Exon 2 of 3	NP_001287907.1	K7EKQ4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAAP24	ENST00000588258.6	TSL:1 MANE Select	c.377C>A	p.Ser126Tyr	missense	Exon 4 of 5	ENSP00000466121.1	Q9BTP7
	FAAP24	ENST00000590281.1	TSL:3	c.377C>A	p.Ser126Tyr	missense	Exon 4 of 5	ENSP00000468475.1	Q9BTP7
	FAAP24	ENST00000699960.1		c.377C>A	p.Ser126Tyr	missense	Exon 4 of 5	ENSP00000514718.1	Q9BTP7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460988 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726804

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

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111796

Other (OTH) AF: 0.00 AC: 0 AN: 60354

⚠️ 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.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.0
Sift4G	Uncertain	0.0040	D
Polyphen		0.96	D
Vest4		0.73
MutPred		0.34		Gain of helix (P = 0.132)
MVP		0.39
MPC		0.96
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.60
gMVP		0.75
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs36017455; hg19: chr19-33465099;