rs142906652

chr15-89268467-T-C

Variant summary

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

The NM_001113378.2(FANCI):c.824T>C(p.Ile275Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000649 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 3.81

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 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=0.02328512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCI	NM_001113378.2	c.824T>C	p.Ile275Thr	missense_variant	10/38	ENST00000310775.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCI	ENST00000310775.12	c.824T>C	p.Ile275Thr	missense_variant	10/38	1	NM_001113378.2	P1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000553 AC: 139 AN: 251470 Hom.: 0 AF XY: 0.000596 AC XY: 81 AN XY: 135912

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000646 AC: 945 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 489 AN XY: 727230

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000815

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74466

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000914 Hom.: 0

Bravo AF: 0.000597

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000560 AC: 68

EpiCase AF: 0.000654

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group I Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 12, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Fanconi anemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 275 of the FANCI protein (p.Ile275Thr). This variant is present in population databases (rs142906652, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with head and neck squamous cell carcinoma or breast cancer (PMID: 28678401, 30303537). ClinVar contains an entry for this variant (Variation ID: 449021). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCI protein function. 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 07, 2022	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2017	The I275T variant in the FANCI gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I275T variant is observed in 64/66740 (0.095%) alleles from individuals of non-Finnish European background, in the ExAC dataset and no individuals were reported to be homozygous (Lek et al., 2016). The I275T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I275T as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2023	Variant summary: FANCI c.824T>C (p.Ile275Thr) results in a non-conservative amino acid change located in the FANCI solenoid 1 domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 251470 control chromosomes. The observed variant frequency is approximately 1.98 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCI causing Fanconi Anemia phenotype (0.00028), strongly suggesting that the variant is benign. c.824T>C has been reported in the literature in individuals affected with various cancer phenotypes including colorectal, head and neck and breast cancer (Poliani_2022, Chandrasekharappa_2018, Girard_2019). These reports do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28678401, 30303537, 36356413). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 23, 2020	DNA sequence analysis of the FANCI gene demonstrated a sequence change, c.824T>C, in exon 10 that results in an amino acid change, p.Ile275Thr. This sequence change has been described in the gnomAD database with a frequency of 0.11% in the European sub-population (dbSNP rs142906652). The p.Ile275Thr change has been described in one individual with head and neck squamous cell carcinoma (PMID: 28678401). The p.Ile275Thr change affects a highly conserved amino acid residue located in a domain of the FANCI protein that is not known to be functional. In-silico predictions pathogenicity prediction tools (SIFT, PoluPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile275Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile275Thr change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.094
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.0	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.022	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.62	P;B;.
Vest4		0.59
MVP		0.80
MPC		0.021
ClinPred		0.046	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.53

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: rs142906652; hg19: chr15-89811698;