rs144908351

Variant names:

• chr15-89281825-A-G
• rs144908351
• NM_001113378.2:c.1573A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001113378.2(FANCI):​c.1573A>G​(p.Met525Val) variant causes a missense change. The variant allele was found at a frequency of 0.00367 in 1,613,740 control chromosomes in the GnomAD database, including 23 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 0.0027 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (18 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 6.81
• Publications: 18 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011244476).
• BP6: Variant 15-89281825-A-G is Benign according to our data. Variant chr15-89281825-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238309.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00269 (409/152282) while in subpopulation NFE AF = 0.00404 (275/68024). AF 95% confidence interval is 0.00365. There are 5 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1573A>G	p.Met525Val	missense	Exon 16 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.1573A>G	p.Met525Val	missense	Exon 16 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.1573A>G	p.Met525Val	missense	Exon 16 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.1573A>G	p.Met525Val	missense	Exon 16 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.1573A>G	p.Met525Val	missense	Exon 16 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.1573A>G	p.Met525Val	missense	Exon 16 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152164 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00230 AC: 577 AN: 251280 AF XY: 0.00215

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00377 AC: 5512 AN: 1461458 Hom.: 18 Cov.: 30 AF XY: 0.00369 AC XY: 2684 AN XY: 727040

African (AFR) AF: 0.000597 AC: 20 AN: 33478

American (AMR) AF: 0.000626 AC: 28 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86248

European-Finnish (FIN) AF: 0.00113 AC: 60 AN: 53272

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00466 AC: 5181 AN: 1111792

Other (OTH) AF: 0.00202 AC: 122 AN: 60388

GnomAD4 genome AF: 0.00269 AC: 409 AN: 152282 Hom.: 5 Cov.: 33 AF XY: 0.00252 AC XY: 188 AN XY: 74464

African (AFR) AF: 0.000650 AC: 27 AN: 41558

American (AMR) AF: 0.000654 AC: 10 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00320 Hom.: 5

Bravo AF: 0.00255

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00213 AC: 259

EpiCase AF: 0.00333

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		0.50	P
Vest4		0.65
MVP		0.66
MPC		0.021
ClinPred		0.056	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.63
Mutation Taster		=93/7	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: rs144908351; hg19: chr15-89825056; COSMIC: COSV99037501; COSMIC: COSV99037501;