15-89278679-C-T

Variant names:

• chr15-89278679-C-T
• rs16942931
• NM_001113378.2:c.1294-8C>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.1294-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 1,608,936 control chromosomes in the GnomAD database, including 460 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (247 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (213 hom.)
• Consequence: FANCI NM_001113378.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003345
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.434
• Publications: 2 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 (BayesDel_noAF=-0.83).
• BP6: Variant 15-89278679-C-T is Benign according to our data. Variant chr15-89278679-C-T is described in ClinVar as Benign. ClinVar VariationId is 317274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 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.1294-8C>T		splice_region intron	N/A	NP_001106849.1
	FANCI	NM_001376911.1		c.1294-8C>T		splice_region intron	N/A	NP_001363840.1
	FANCI	NM_018193.3		c.1294-8C>T		splice_region intron	N/A	NP_060663.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.1294-8C>T		splice_region intron	N/A	ENSP00000310842.8
	FANCI	ENST00000674831.1		c.1294-8C>T		splice_region intron	N/A	ENSP00000502474.1
	FANCI	ENST00000940814.1		c.1294-8C>T		splice_region intron	N/A	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4634 AN: 152140 Hom.: 246 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.00818 AC: 2052 AN: 250816 AF XY: 0.00611

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00613

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000846

Gnomad OTH exome AF: 0.00688

GnomAD4 exome AF: 0.00358 AC: 5210 AN: 1456678 Hom.: 213 Cov.: 29 AF XY: 0.00326 AC XY: 2366 AN XY: 725170

African (AFR) AF: 0.106 AC: 3525 AN: 33300

American (AMR) AF: 0.00750 AC: 335 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.000453 AC: 39 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5760

European-Non Finnish (NFE) AF: 0.000643 AC: 712 AN: 1107534

Other (OTH) AF: 0.00825 AC: 497 AN: 60218

GnomAD4 genome AF: 0.0306 AC: 4652 AN: 152258 Hom.: 247 Cov.: 33 AF XY: 0.0286 AC XY: 2130 AN XY: 74452

African (AFR) AF: 0.104 AC: 4328 AN: 41556

American (AMR) AF: 0.0138 AC: 211 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68018

Other (OTH) AF: 0.0208 AC: 44 AN: 2116

Alfa AF: 0.0156 Hom.: 67

Bravo AF: 0.0356

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group I (3)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.7
DANN	Benign	0.65
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0060
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: rs16942931; hg19: chr15-89821910; COSMIC: COSV104536595;