15-89293908-G-T

Variant names:

• chr15-89293908-G-T
• rs11857960
• NM_001113378.2:c.2367G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001113378.2(FANCI):​c.2367G>T​(p.Ala789Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,613,882 control chromosomes in the GnomAD database, including 2,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A789A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.074 (1201 hom., cov: 32)
  • Exomes 𝑓: 0.011 (1169 hom.)
• Consequence: FANCI NM_001113378.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.257
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 15-89293908-G-T is Benign according to our data. Variant chr15-89293908-G-T is described in ClinVar as Benign. ClinVar VariationId is 257483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.257 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 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.2367G>T	p.Ala789Ala	synonymous	Exon 23 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.2367G>T	p.Ala789Ala	synonymous	Exon 23 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.2367G>T	p.Ala789Ala	synonymous	Exon 23 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.2367G>T	p.Ala789Ala	synonymous	Exon 23 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.2367G>T	p.Ala789Ala	synonymous	Exon 23 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.2391G>T	p.Ala797Ala	synonymous	Exon 23 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.0735 AC: 11167 AN: 151960 Hom.: 1199 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0422

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.0603

GnomAD2 exomes AF: 0.0247 AC: 6222 AN: 251430 AF XY: 0.0198

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0137

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0109 AC: 16002 AN: 1461806 Hom.: 1169 Cov.: 31 AF XY: 0.0102 AC XY: 7403 AN XY: 727204

African (AFR) AF: 0.244 AC: 8178 AN: 33470

American (AMR) AF: 0.0222 AC: 992 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00383 AC: 100 AN: 26132

East Asian (EAS) AF: 0.0145 AC: 575 AN: 39676

South Asian (SAS) AF: 0.00681 AC: 587 AN: 86256

European-Finnish (FIN) AF: 0.0240 AC: 1282 AN: 53414

Middle Eastern (MID) AF: 0.0496 AC: 286 AN: 5768

European-Non Finnish (NFE) AF: 0.00230 AC: 2562 AN: 1111976

Other (OTH) AF: 0.0238 AC: 1440 AN: 60390

GnomAD4 genome AF: 0.0736 AC: 11195 AN: 152076 Hom.: 1201 Cov.: 32 AF XY: 0.0713 AC XY: 5305 AN XY: 74352

African (AFR) AF: 0.238 AC: 9840 AN: 41426

American (AMR) AF: 0.0421 AC: 644 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0149 AC: 77 AN: 5176

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4820

European-Finnish (FIN) AF: 0.0225 AC: 238 AN: 10582

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 68002

Other (OTH) AF: 0.0597 AC: 126 AN: 2112

Alfa AF: 0.0342 Hom.: 399

Bravo AF: 0.0839

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

ClinVar submissions

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.9
DANN	Benign	0.56
PhyloP100		0.26
Mutation Taster		=97/3	polymorphism (auto)

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: rs11857960; hg19: chr15-89837139; COSMIC: COSV55524731; COSMIC: COSV55524731;