rs62020347

Variant names:

• chr15-89260719-C-T
• rs62020347
• NM_001113378.2:c.164C>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.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:8
• Conservation: PhyloP100: 6.63
• Publications: 26 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=0.0022953153).
• BP6: Variant 15-89260719-C-T is Benign according to our data. Variant chr15-89260719-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

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.164C>T	p.Pro55Leu	missense	Exon 4 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.164C>T	p.Pro55Leu	missense	Exon 4 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.164C>T	p.Pro55Leu	missense	Exon 4 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.164C>T	p.Pro55Leu	missense	Exon 4 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000567996.5	TSL:1	c.164C>T	p.Pro55Leu	missense	Exon 6 of 11	ENSP00000458024.1	Q9NVI1-4
	FANCI	ENST00000674831.1		c.164C>T	p.Pro55Leu	missense	Exon 4 of 39	ENSP00000502474.1	A0A6Q8PH09

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

GnomAD2 exomes AF: 0.0527 AC: 13246 AN: 251442 AF XY: 0.0559

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 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

African (AFR) AF: 0.0200 AC: 670 AN: 33478

American (AMR) AF: 0.0347 AC: 1550 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 2324 AN: 26094

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39676

South Asian (SAS) AF: 0.0745 AC: 6424 AN: 86228

European-Finnish (FIN) AF: 0.0273 AC: 1457 AN: 53346

Middle Eastern (MID) AF: 0.0689 AC: 397 AN: 5766

European-Non Finnish (NFE) AF: 0.0643 AC: 71460 AN: 1111704

Other (OTH) AF: 0.0556 AC: 3356 AN: 60358

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

African (AFR) AF: 0.0214 AC: 888 AN: 41526

American (AMR) AF: 0.0450 AC: 688 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 311 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5188

South Asian (SAS) AF: 0.0789 AC: 380 AN: 4814

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10582

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0646 AC: 4392 AN: 68006

Other (OTH) AF: 0.0530 AC: 112 AN: 2112

Alfa AF: 0.0604 Hom.: 1010

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group I (3)
-	-	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	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.6
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=229/71	polymorphism (auto)

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

Other links and lift over

dbSNP: rs62020347; hg19: chr15-89803950; COSMIC: COSV55530374;