17-81545810-C-G

Variant names:

• chr17-81545810-C-G
• NM_025161.6:c.2246G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025161.6(FAAP100):​c.2246G>C​(p.Arg749Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R749Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAAP100 NM_025161.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.769

Genes affected

FAAP100 (HGNC:26171): (FA core complex associated protein 100) FAAP100 is a component of the Fanconi anemia (FA; MIM 277650) core complex and is required for core complex stability and FANCD2 (see MIM 227646) monoubiquitination (Ling et al., 2007 [PubMed 17396147]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11154127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAAP100	NM_025161.6	c.2246G>C	p.Arg749Pro	missense_variant	Exon 6 of 9	ENST00000327787.13	NP_079437.5
FAAP100	XM_006722111.3	c.1832G>C	p.Arg611Pro	missense_variant	Exon 6 of 9		XP_006722174.1
FAAP100	XM_047436848.1	c.1793G>C	p.Arg598Pro	missense_variant	Exon 5 of 8		XP_047292804.1
FAAP100	NR_033338.2	n.2465G>C		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAAP100	ENST00000327787.13	c.2246G>C	p.Arg749Pro	missense_variant	Exon 6 of 9	1	NM_025161.6	ENSP00000333283.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2246G>C (p.R749P) alteration is located in exon 6 (coding exon 6) of the FAAP100 gene. This alteration results from a G to C substitution at nucleotide position 2246, causing the arginine (R) at amino acid position 749 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	Benign	0.29
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	4.0
DANN	Benign	0.94
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
PROVEAN	Benign	-0.81	N;N
REVEL	Benign	0.14
Sift	Benign	0.24	T;T
Sift4G	Uncertain	0.051	T;T
Polyphen		0.74	P;P
Vest4		0.20
MutPred		0.42		Loss of helix (P = 0.0072);.;
MVP		0.17
MPC		0.52
ClinPred		0.13	T
GERP RS		-3.9
Varity_R		0.13
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-79512836;