15-89294945-T-G

Variant names:

• chr15-89294945-T-G
• rs145762491
• NM_001113378.2:c.2487T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001113378.2(FANCI):​c.2487T>G​(p.Leu829Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,552,344 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (10 hom.)
• Consequence: FANCI NM_001113378.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.986
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 15-89294945-T-G is Benign according to our data. Variant chr15-89294945-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210986.
• BP7: Synonymous conserved (PhyloP=0.986 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0018 (2517/1400038) while in subpopulation MID AF = 0.0205 (117/5702). AF 95% confidence interval is 0.0175. There are 10 homozygotes in GnomAdExome4. There are 1314 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.2487T>G	p.Leu829Leu	synonymous	Exon 24 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.2487T>G	p.Leu829Leu	synonymous	Exon 24 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_001376910.1		c.2208T>G	p.Leu736Leu	synonymous	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.2487T>G	p.Leu829Leu	synonymous	Exon 24 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.2487T>G	p.Leu829Leu	synonymous	Exon 24 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.2511T>G	p.Leu837Leu	synonymous	Exon 24 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00210 AC: 333 AN: 158914 AF XY: 0.00216

Gnomad AFR exome AF: 0.000240

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00386

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00105

Gnomad NFE exome AF: 0.00266

Gnomad OTH exome AF: 0.00752

GnomAD4 exome AF: 0.00180 AC: 2517 AN: 1400038 Hom.: 10 Cov.: 31 AF XY: 0.00190 AC XY: 1314 AN XY: 690490

African (AFR) AF: 0.000791 AC: 25 AN: 31598

American (AMR) AF: 0.00353 AC: 126 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 88 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.000984 AC: 78 AN: 79230

European-Finnish (FIN) AF: 0.000827 AC: 41 AN: 49582

Middle Eastern (MID) AF: 0.0205 AC: 117 AN: 5702

European-Non Finnish (NFE) AF: 0.00173 AC: 1869 AN: 1079104

Other (OTH) AF: 0.00297 AC: 173 AN: 58196

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74472

African (AFR) AF: 0.0000962 AC: 4 AN: 41574

American (AMR) AF: 0.00255 AC: 39 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00225 AC: 153 AN: 68030

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00215 Hom.: 1

Bravo AF: 0.00186

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Fanconi anemia complementation group I (3)
-	-	2	Fanconi anemia (2)
-	-	1	FANCI-related disorder (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.1
DANN	Benign	0.78
PhyloP100		0.99
Mutation Taster		=98/2	polymorphism

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: rs145762491; hg19: chr15-89838176; COSMIC: COSV55522771; COSMIC: COSV55522771;