15-89276777-T-C

Variant names:

• chr15-89276777-T-C
• rs3743377
• NM_001113378.2:c.1179T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001113378.2(FANCI):​c.1179T>C​(p.Tyr393Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,614,208 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (85 hom.)
• Consequence: FANCI NM_001113378.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.648
• Publications: 8 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 15-89276777-T-C is Benign according to our data. Variant chr15-89276777-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.648 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0574 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.1179T>C	p.Tyr393Tyr	synonymous	Exon 13 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.1179T>C	p.Tyr393Tyr	synonymous	Exon 13 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.1179T>C	p.Tyr393Tyr	synonymous	Exon 13 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.1179T>C	p.Tyr393Tyr	synonymous	Exon 13 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.1179T>C	p.Tyr393Tyr	synonymous	Exon 13 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.1179T>C	p.Tyr393Tyr	synonymous	Exon 13 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152228 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0465

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00572 AC: 1438 AN: 251428 AF XY: 0.00496

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0387

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00288 AC: 4212 AN: 1461862 Hom.: 85 Cov.: 31 AF XY: 0.00285 AC XY: 2071 AN XY: 727234

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0145 AC: 650 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26132

East Asian (EAS) AF: 0.0594 AC: 2356 AN: 39692

South Asian (SAS) AF: 0.00163 AC: 141 AN: 86258

European-Finnish (FIN) AF: 0.00221 AC: 118 AN: 53414

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000682 AC: 758 AN: 1112000

Other (OTH) AF: 0.00273 AC: 165 AN: 60394

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152346 Hom.: 6 Cov.: 32 AF XY: 0.00348 AC XY: 259 AN XY: 74510

African (AFR) AF: 0.000649 AC: 27 AN: 41588

American (AMR) AF: 0.00581 AC: 89 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.0464 AC: 240 AN: 5176

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00345

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group I (4)
-	-	1	FANCI-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.9
DANN	Benign	0.29
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

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: rs3743377; hg19: chr15-89820008;