17-81545882-C-T

Variant names:

• chr17-81545882-C-T
• rs199924077
• NM_025161.6:c.2174G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025161.6(FAAP100):​c.2174G>A​(p.Gly725Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,605,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: FAAP100 NM_025161.6 missense, splice_region
• Scores: Splicing: ADA: 0.01381
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.339

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027916878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAAP100	NM_025161.6	c.2174G>A	p.Gly725Asp	missense_variant, splice_region_variant	Exon 6 of 9	ENST00000327787.13	NP_079437.5
FAAP100	XM_006722111.3	c.1760G>A	p.Gly587Asp	missense_variant, splice_region_variant	Exon 6 of 9		XP_006722174.1
FAAP100	XM_047436848.1	c.1721G>A	p.Gly574Asp	missense_variant, splice_region_variant	Exon 5 of 8		XP_047292804.1
FAAP100	NR_033338.2	n.2393G>A		splice_region_variant, 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.2174G>A	p.Gly725Asp	missense_variant, splice_region_variant	Exon 6 of 9	1	NM_025161.6	ENSP00000333283.8

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000221 AC: 53 AN: 240006 Hom.: 0 AF XY: 0.000206 AC XY: 27 AN XY: 131100

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.000813

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000236

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.000138 AC: 200 AN: 1452790 Hom.: 0 Cov.: 31 AF XY: 0.000124 AC XY: 90 AN XY: 722932

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.000768

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000223 AC: 27

EpiCase AF: 0.000164

EpiControl AF: 0.000475

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2174G>A (p.G725D) alteration is located in exon 6 (coding exon 6) of the FAAP100 gene. This alteration results from a G to A substitution at nucleotide position 2174, causing the glycine (G) at amino acid position 725 to be replaced by an aspartic acid (D). 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	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.31
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.073
Sift	Benign	0.59	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.015	B;B
Vest4		0.24
MVP		0.14
MPC		0.79
ClinPred		0.025	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -29

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

Publications

LitVar

Other links and lift over

dbSNP: rs199924077; hg19: chr17-79512908;