15-89301433-C-T

Variant names:

• chr15-89301433-C-T
• rs138675752
• NM_001113378.2:c.2997C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001113378.2(FANCI):​c.2997C>T​(p.Ser999Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,610,410 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (25 hom.)
• Consequence: FANCI NM_001113378.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.548
• Publications: 4 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

LOC124903548 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 15-89301433-C-T is Benign according to our data. Variant chr15-89301433-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.548 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00264 (402/152320) while in subpopulation SAS AF = 0.00704 (34/4830). AF 95% confidence interval is 0.00518. There are 0 homozygotes in GnomAd4. There are 201 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 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.2997C>T	p.Ser999Ser	synonymous	Exon 27 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.2997C>T	p.Ser999Ser	synonymous	Exon 27 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.2817C>T	p.Ser939Ser	synonymous	Exon 26 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.2997C>T	p.Ser999Ser	synonymous	Exon 27 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.2997C>T	p.Ser999Ser	synonymous	Exon 27 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.3021C>T	p.Ser1007Ser	synonymous	Exon 27 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00297 AC: 748 AN: 251480 AF XY: 0.00323

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00332 AC: 4837 AN: 1458090 Hom.: 25 Cov.: 29 AF XY: 0.00358 AC XY: 2596 AN XY: 725674

African (AFR) AF: 0.000599 AC: 20 AN: 33398

American (AMR) AF: 0.00195 AC: 87 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 77 AN: 26098

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.00696 AC: 600 AN: 86190

European-Finnish (FIN) AF: 0.00285 AC: 152 AN: 53420

Middle Eastern (MID) AF: 0.00712 AC: 41 AN: 5760

European-Non Finnish (NFE) AF: 0.00329 AC: 3647 AN: 1108566

Other (OTH) AF: 0.00350 AC: 211 AN: 60262

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74492

African (AFR) AF: 0.000890 AC: 37 AN: 41574

American (AMR) AF: 0.00150 AC: 23 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4830

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00379 AC: 258 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00322 Hom.: 1

Bravo AF: 0.00234

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00445

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Fanconi anemia (2)
-	-	2	Fanconi anemia complementation group I (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	4.4
DANN	Benign	0.63
PhyloP100		-0.55
Mutation Taster		=100/0	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: rs138675752; hg19: chr15-89844664; COSMIC: COSV55527971; COSMIC: COSV55527971;