rs575416245

Variant names:

• chr15-89273399-A-G
• rs575416245
• NM_001113378.2:c.905A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-89273399-A-G
• chr15-89273399-A-C
• chr15-89273399-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001113378.2(FANCI):​c.905A>G​(p.Asn302Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,605,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.185
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021826029).

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.905A>G	p.Asn302Ser	missense	Exon 11 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.905A>G	p.Asn302Ser	missense	Exon 11 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.905A>G	p.Asn302Ser	missense	Exon 11 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.905A>G	p.Asn302Ser	missense	Exon 11 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.905A>G	p.Asn302Ser	missense	Exon 11 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.905A>G	p.Asn302Ser	missense	Exon 11 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151440 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251018 AF XY: 0.0000590

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000310 AC: 45 AN: 1453778 Hom.: 0 Cov.: 30 AF XY: 0.0000373 AC XY: 27 AN XY: 723728

African (AFR) AF: 0.0000300 AC: 1 AN: 33288

American (AMR) AF: 0.0000672 AC: 3 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39602

South Asian (SAS) AF: 0.000257 AC: 22 AN: 85722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1105216

Other (OTH) AF: 0.0000166 AC: 1 AN: 60116

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151556 Hom.: 0 Cov.: 28 AF XY: 0.0000135 AC XY: 1 AN XY: 74080

African (AFR) AF: 0.00 AC: 0 AN: 41334

American (AMR) AF: 0.00 AC: 0 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)
-	1	-	Fanconi anemia complementation group I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.047
DANN	Benign	0.13
DEOGEN2	Benign	0.031	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.18
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.054
Sift	Benign	0.98	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.17		Gain of disorder (P = 0.073)
MVP		0.33
MPC		0.015
ClinPred		0.015	T
GERP RS		-6.0
Varity_R		0.032
gMVP		0.056
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs575416245; hg19: chr15-89816630; COSMIC: COSV100167818; COSMIC: COSV100167818;