15-89292997-G-C

Variant names:

• chr15-89292997-G-C
• rs2283432
• NM_001113378.2:c.2225G>C

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.2225G>C​(p.Cys742Ser) variant causes a missense change. The variant allele was found at a frequency of 0.369 in 1,613,342 control chromosomes in the GnomAD database, including 114,402 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. C742R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (8407 hom., cov: 32)
  • Exomes 𝑓: 0.38 (105995 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.96
• Publications: 58 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=0.0024511814).
• BP6: Variant 15-89292997-G-C is Benign according to our data. Variant chr15-89292997-G-C is described in ClinVar as Benign. ClinVar VariationId is 257482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.386 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.2225G>C	p.Cys742Ser	missense	Exon 22 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.2225G>C	p.Cys742Ser	missense	Exon 22 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.2225G>C	p.Cys742Ser	missense	Exon 22 of 37	NP_060663.2	Q9NVI1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.2225G>C	p.Cys742Ser	missense	Exon 22 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.2225G>C	p.Cys742Ser	missense	Exon 22 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.2225G>C	p.Cys742Ser	missense	Exon 22 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45914 AN: 152012 Hom.: 8406 Cov.: 32

Gnomad AFR AF: 0.0888

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.365 AC: 91607 AN: 251090 AF XY: 0.373

Gnomad AFR exome AF: 0.0801

Gnomad AMR exome AF: 0.365

Gnomad ASJ exome AF: 0.379

Gnomad EAS exome AF: 0.328

Gnomad FIN exome AF: 0.462

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.376 AC: 549860 AN: 1461212 Hom.: 105995 Cov.: 35 AF XY: 0.378 AC XY: 274832 AN XY: 726930

African (AFR) AF: 0.0740 AC: 2478 AN: 33474

American (AMR) AF: 0.359 AC: 16049 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 10002 AN: 26124

East Asian (EAS) AF: 0.313 AC: 12395 AN: 39664

South Asian (SAS) AF: 0.392 AC: 33849 AN: 86242

European-Finnish (FIN) AF: 0.455 AC: 24308 AN: 53396

Middle Eastern (MID) AF: 0.330 AC: 1899 AN: 5756

European-Non Finnish (NFE) AF: 0.384 AC: 426805 AN: 1111470

Other (OTH) AF: 0.366 AC: 22075 AN: 60366

GnomAD4 genome AF: 0.302 AC: 45912 AN: 152130 Hom.: 8407 Cov.: 32 AF XY: 0.310 AC XY: 23045 AN XY: 74372

African (AFR) AF: 0.0887 AC: 3683 AN: 41536

American (AMR) AF: 0.317 AC: 4842 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1281 AN: 3466

East Asian (EAS) AF: 0.325 AC: 1685 AN: 5184

South Asian (SAS) AF: 0.385 AC: 1856 AN: 4822

European-Finnish (FIN) AF: 0.469 AC: 4949 AN: 10560

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.390 AC: 26523 AN: 67962

Other (OTH) AF: 0.308 AC: 649 AN: 2110

Alfa AF: 0.336 Hom.: 2887

Bravo AF: 0.284

TwinsUK AF: 0.374 AC: 1388

ALSPAC AF: 0.354 AC: 1364

ESP6500AA AF: 0.0953 AC: 419

ESP6500EA AF: 0.390 AC: 3349

ExAC AF: 0.362 AC: 43937

Asia WGS AF: 0.331 AC: 1149 AN: 3478

EpiCase AF: 0.379

EpiControl AF: 0.381

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)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.070	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	M
PhyloP100		5.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.075
Sift	Benign	0.50	T
Sift4G	Uncertain	0.033	D
Polyphen		0.66	P
Vest4		0.18
MutPred		0.18		Gain of disorder (P = 0.0463)
MPC		0.016
ClinPred		0.023	T
GERP RS		4.9
Varity_R		0.11
gMVP		0.21
Mutation Taster		=91/9	polymorphism (auto)

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: rs2283432; hg19: chr15-89836228; COSMIC: COSV55522176; COSMIC: COSV55522176;