rs370996106

chr15-89293996-A-G

Variant summary

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

The NM_001113378.2(FANCI):c.2455A>G(p.Arg819Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCI NM_001113378.2 missense, splice_region
• Scores: Splicing: ADA: 0.9963
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.84

Genes affected

FANCI (HGNC:25568): (FA complementation group I) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group I. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCI	NM_001113378.2	c.2455A>G	p.Arg819Gly	missense_variant, splice_region_variant	23/38	ENST00000310775.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCI	ENST00000310775.12	c.2455A>G	p.Arg819Gly	missense_variant, splice_region_variant	23/38	1	NM_001113378.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135874

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 04, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 570964). This variant has not been reported in the literature in individuals affected with FANCI-related conditions. This variant is present in population databases (rs370996106, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 819 of the FANCI protein (p.Arg819Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.55	T;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D;N
REVEL	Uncertain	0.41
Sift	Benign	0.15	T;T
Sift4G	Uncertain	0.013	D;D
Polyphen		0.83	P;P
Vest4		0.61
MVP		0.90
MPC		0.028
ClinPred		0.53	D
GERP RS		5.7
Varity_R		0.26
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs370996106; hg19: chr15-89837227;