rs772401747

Variant names:

• chr15-89303913-G-A
• rs772401747
• NM_001113378.2:c.3056G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-89303913-G-A
• chr15-89303913-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001113378.2(FANCI):​c.3056G>A​(p.Arg1019Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1019W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: FANCI NM_001113378.2 missense, splice_region
• Scores: Splicing: ADA: 0.00001446
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.527
• Publications: 3 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124903548 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001113378.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044164956).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	NM_001113378.2	MANE Select	c.3056G>A	p.Arg1019Gln	missense splice_region	Exon 28 of 38	NP_001106849.1
	FANCI	NM_001376911.1		c.3056G>A	p.Arg1019Gln	missense splice_region	Exon 28 of 38	NP_001363840.1
	FANCI	NM_018193.3		c.2876G>A	p.Arg959Gln	missense splice_region	Exon 27 of 37	NP_060663.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.3056G>A	p.Arg1019Gln	missense splice_region	Exon 28 of 38	ENSP00000310842.8
	FANCI	ENST00000674831.1		c.3056G>A	p.Arg1019Gln	missense splice_region	Exon 28 of 39	ENSP00000502474.1
	FANCI	ENST00000696719.1		c.3056G>A	p.Arg1019Gln	missense splice_region	Exon 29 of 39	ENSP00000512832.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251428 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461526 Hom.: 0 Cov.: 30 AF XY: 0.0000894 AC XY: 65 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000113 AC: 126 AN: 1111708

Other (OTH) AF: 0.0000497 AC: 3 AN: 60382

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.0000965 AC: 4 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	6.8
DANN	Benign	0.91
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N
PhyloP100		0.53
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.13
Sift	Benign	0.33	T
Sift4G	Benign	0.36	T
Polyphen		0.061	B
Vest4		0.16
MVP		0.40
MPC		0.016
ClinPred		0.057	T
GERP RS		-8.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.099
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.034
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: rs772401747; hg19: chr15-89847144; COSMIC: COSV55536301; COSMIC: COSV55536301;