rs149243307

Variant names:

• chr15-89260841-G-A
• rs149243307
• NM_001113378.2:c.286G>A

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.286G>A​(p.Glu96Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000594 in 1,613,630 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00079 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (2 hom.)
• Consequence: FANCI NM_001113378.2 missense, splice_region
• Scores: Splicing: ADA: 0.9395
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 8.90
• Publications: 17 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=0.008752376).
• BP6: Variant 15-89260841-G-A is Benign according to our data. Variant chr15-89260841-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000788 (120/152304) while in subpopulation EAS AF = 0.016 (83/5178). AF 95% confidence interval is 0.0132. There are 2 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	NM_001113378.2	MANE Select	c.286G>A	p.Glu96Lys	missense splice_region	Exon 4 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.286G>A	p.Glu96Lys	missense splice_region	Exon 4 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.286G>A	p.Glu96Lys	missense splice_region	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.286G>A	p.Glu96Lys	missense splice_region	Exon 4 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000567996.5	TSL:1	c.286G>A	p.Glu96Lys	missense splice_region	Exon 6 of 11	ENSP00000458024.1	Q9NVI1-4
	FANCI	ENST00000674831.1		c.286G>A	p.Glu96Lys	missense splice_region	Exon 4 of 39	ENSP00000502474.1	A0A6Q8PH09

Frequencies

GnomAD3 genomes AF: 0.000795 AC: 121 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00174 AC: 437 AN: 251450 AF XY: 0.00180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0187

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000573 AC: 838 AN: 1461326 Hom.: 2 Cov.: 36 AF XY: 0.000601 AC XY: 437 AN XY: 726972

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0119 AC: 471 AN: 39658

South Asian (SAS) AF: 0.000731 AC: 63 AN: 86226

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53338

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111662

Other (OTH) AF: 0.000994 AC: 60 AN: 60368

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74476

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.000131 AC: 2 AN: 15300

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

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000773 Hom.: 3

Bravo AF: 0.000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00162 AC: 197

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		8.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.81
MPC		0.11
ClinPred		0.068	T
GERP RS		5.4
Varity_R		0.65
gMVP		0.78
Mutation Taster		=176/124	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.83
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: rs149243307; hg19: chr15-89804072;