NM_001113378.2:c.1211T>C

Variant names:

• chr15-89276809-T-C
• rs79080874
• NM_001113378.2:c.1211T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001113378.2(FANCI):​c.1211T>C​(p.Ile404Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000734 in 1,614,208 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I404I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (6 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.52
• Publications: 6 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: ClinGen, Labcorp Genetics (formerly Invitae), 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=0.0043126047).
• BP6: Variant 15-89276809-T-C is Benign according to our data. Variant chr15-89276809-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00373 (568/152350) while in subpopulation AFR AF = 0.0132 (547/41586). AF 95% confidence interval is 0.0122. There are 5 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	NM_001113378.2	MANE Select	c.1211T>C	p.Ile404Thr	missense	Exon 13 of 38	NP_001106849.1
	FANCI	NM_001376911.1		c.1211T>C	p.Ile404Thr	missense	Exon 13 of 38	NP_001363840.1
	FANCI	NM_018193.3		c.1211T>C	p.Ile404Thr	missense	Exon 13 of 37	NP_060663.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.1211T>C	p.Ile404Thr	missense	Exon 13 of 38	ENSP00000310842.8
	FANCI	ENST00000674831.1		c.1211T>C	p.Ile404Thr	missense	Exon 13 of 39	ENSP00000502474.1
	FANCI	ENST00000696719.1		c.1211T>C	p.Ile404Thr	missense	Exon 14 of 39	ENSP00000512832.1

Frequencies

GnomAD3 genomes AF: 0.00372 AC: 566 AN: 152232 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00101 AC: 253 AN: 251442 AF XY: 0.000692

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000422 AC: 617 AN: 1461858 Hom.: 6 Cov.: 31 AF XY: 0.000364 AC XY: 265 AN XY: 727228

African (AFR) AF: 0.0152 AC: 508 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111998

Other (OTH) AF: 0.000795 AC: 48 AN: 60394

GnomAD4 genome AF: 0.00373 AC: 568 AN: 152350 Hom.: 5 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74508

African (AFR) AF: 0.0132 AC: 547 AN: 41586

American (AMR) AF: 0.000914 AC: 14 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00133 Hom.: 4

Bravo AF: 0.00450

ESP6500AA AF: 0.00886 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCI: BP4, BS1

Mar 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Fanconi anemia complementation group I Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.4
DANN	Benign	0.83
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.15	N
PhyloP100		1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.095
Sift	Benign	0.47	T
Sift4G	Benign	0.39	T
Polyphen		0.0010	B
Vest4		0.078
MVP		0.44
MPC		0.016
ClinPred		0.0017	T
GERP RS		2.1
Varity_R		0.028
gMVP		0.13
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79080874; hg19: chr15-89820040; COSMIC: COSV104595276;