rs62020347

chr15-89260719-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001113378.2(FANCI):c.164C>T(p.Pro55Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0588 in 1,613,550 control chromosomes in the GnomAD database, including 3,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P55S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.047 (222 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2889 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.63

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022953153).
• BP6: Variant 15-89260719-C-T is Benign according to our data. Variant chr15-89260719-C-T is described in ClinVar as [Benign]. Clinvar id is 257480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCI	NM_001113378.2	c.164C>T	p.Pro55Leu	missense_variant	4/38	ENST00000310775.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCI	ENST00000310775.12	c.164C>T	p.Pro55Leu	missense_variant	4/38	1	NM_001113378.2	P1

Frequencies

GnomAD3 genomes AF: 0.0470 AC: 7152 AN: 152070 Hom.: 223 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0896

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0803

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.0536

GnomAD3 exomes AF: 0.0527 AC: 13246 AN: 251442 Hom.: 468 AF XY: 0.0559 AC XY: 7603 AN XY: 135898

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.0867

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0757

Gnomad FIN exome AF: 0.0264

Gnomad NFE exome AF: 0.0667

Gnomad OTH exome AF: 0.0593

GnomAD4 exome AF: 0.0600 AC: 87652 AN: 1461362 Hom.: 2889 Cov.: 31 AF XY: 0.0608 AC XY: 44173 AN XY: 727026

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.0347

Gnomad4 ASJ exome AF: 0.0891

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0745

Gnomad4 FIN exome AF: 0.0273

Gnomad4 NFE exome AF: 0.0643

Gnomad4 OTH exome AF: 0.0556

GnomAD4 genome AF: 0.0469 AC: 7145 AN: 152188 Hom.: 222 Cov.: 32 AF XY: 0.0459 AC XY: 3414 AN XY: 74400

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.0450

Gnomad4 ASJ AF: 0.0896

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0789

Gnomad4 FIN AF: 0.0232

Gnomad4 NFE AF: 0.0646

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0622 Hom.: 499

Bravo AF: 0.0467

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0654 AC: 252

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.0678 AC: 583

ExAC AF: 0.0546 AC: 6628

Asia WGS AF: 0.0450 AC: 157 AN: 3478

EpiCase AF: 0.0683

EpiControl AF: 0.0656

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 07, 2016	- -

Fanconi anemia complementation group I Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D
MetaRNN	Benign	0.0023	T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.8	M;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N;D;D;D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.78
MPC		0.088
ClinPred		0.015	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs62020347; hg19: chr15-89803950; COSMIC: COSV55530374; COSMIC: COSV55530374;