rs35875311

Variant names:

• chr15-89295087-A-T
• rs35875311
• NM_001113378.2:c.2629A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001113378.2(FANCI):​c.2629A>T​(p.Ile877Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0967 in 1,551,466 control chromosomes in the GnomAD database, including 7,822 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I877V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.074 (561 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7261 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.84
• Publications: 16 publications found

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]

FANCI Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group I

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016543865).
• BP6: Variant 15-89295087-A-T is Benign according to our data. Variant chr15-89295087-A-T is described in ClinVar as Benign. ClinVar VariationId is 257485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113378.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	NM_001113378.2	MANE Select	c.2629A>T	p.Ile877Leu	missense	Exon 24 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.2629A>T	p.Ile877Leu	missense	Exon 24 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_001376910.1		c.2350A>T	p.Ile784Leu	missense	Exon 24 of 38	NP_001363839.1	A0A8Q3SIW9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.2629A>T	p.Ile877Leu	missense	Exon 24 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.2629A>T	p.Ile877Leu	missense	Exon 24 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.2653A>T	p.Ile885Leu	missense	Exon 24 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.0739 AC: 11252 AN: 152182 Hom.: 561 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0705

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0581

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0934

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0746

GnomAD2 exomes AF: 0.0883 AC: 13805 AN: 156354 AF XY: 0.0911

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.0713

Gnomad ASJ exome AF: 0.0972

Gnomad EAS exome AF: 0.0452

Gnomad FIN exome AF: 0.0986

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0961

GnomAD4 exome AF: 0.0992 AC: 138754 AN: 1399166 Hom.: 7261 Cov.: 32 AF XY: 0.0997 AC XY: 68832 AN XY: 690094

African (AFR) AF: 0.0142 AC: 449 AN: 31578

American (AMR) AF: 0.0708 AC: 2520 AN: 35610

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 2560 AN: 25176

East Asian (EAS) AF: 0.0723 AC: 2583 AN: 35734

South Asian (SAS) AF: 0.107 AC: 8491 AN: 79192

European-Finnish (FIN) AF: 0.0963 AC: 4748 AN: 49300

Middle Eastern (MID) AF: 0.0674 AC: 384 AN: 5694

European-Non Finnish (NFE) AF: 0.103 AC: 111609 AN: 1078886

Other (OTH) AF: 0.0933 AC: 5410 AN: 57996

GnomAD4 genome AF: 0.0739 AC: 11251 AN: 152300 Hom.: 561 Cov.: 32 AF XY: 0.0737 AC XY: 5492 AN XY: 74468

African (AFR) AF: 0.0179 AC: 745 AN: 41582

American (AMR) AF: 0.0704 AC: 1078 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3466

East Asian (EAS) AF: 0.0581 AC: 301 AN: 5184

South Asian (SAS) AF: 0.105 AC: 507 AN: 4832

European-Finnish (FIN) AF: 0.0934 AC: 991 AN: 10612

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 7025 AN: 68002

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.101 Hom.: 602

Bravo AF: 0.0685

TwinsUK AF: 0.0968 AC: 359

ALSPAC AF: 0.0856 AC: 330

ESP6500AA AF: 0.0210 AC: 29

ESP6500EA AF: 0.110 AC: 349

ExAC AF: 0.0880 AC: 2196

Asia WGS AF: 0.104 AC: 361 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group I (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Benign	0.14	T
Polyphen		0.072	B
Vest4		0.13
MutPred		0.34		Loss of MoRF binding (P = 0.1504)
MPC		0.016
ClinPred		0.017	T
GERP RS		6.0
Varity_R		0.11
gMVP		0.39
Mutation Taster		=60/40	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35875311; hg19: chr15-89838318; COSMIC: COSV55522195; COSMIC: COSV55522195;