rs79685648

Variant names:

• chr15-89300328-A-C
• rs79685648
• NM_001113378.2:c.2832A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-89300328-A-C
• chr15-89300328-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001113378.2(FANCI):​c.2832A>C​(p.Arg944Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,613,996 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R944R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (6 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.72
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00412938).
• BP6: Variant 15-89300328-A-C is Benign according to our data. Variant chr15-89300328-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00362 (552/152300) while in subpopulation AFR AF = 0.0128 (531/41558). AF 95% confidence interval is 0.0119. There are 4 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.2832A>C	p.Arg944Ser	missense	Exon 26 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.2832A>C	p.Arg944Ser	missense	Exon 26 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.2652A>C	p.Arg884Ser	missense	Exon 25 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.2832A>C	p.Arg944Ser	missense	Exon 26 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.2832A>C	p.Arg944Ser	missense	Exon 26 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.2856A>C	p.Arg952Ser	missense	Exon 26 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 550 AN: 152182 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000986 AC: 248 AN: 251438 AF XY: 0.000670

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000419 AC: 612 AN: 1461696 Hom.: 6 Cov.: 31 AF XY: 0.000360 AC XY: 262 AN XY: 727164

African (AFR) AF: 0.0150 AC: 503 AN: 33476

American (AMR) AF: 0.000783 AC: 35 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111874

Other (OTH) AF: 0.000811 AC: 49 AN: 60384

GnomAD4 genome AF: 0.00362 AC: 552 AN: 152300 Hom.: 4 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74484

African (AFR) AF: 0.0128 AC: 531 AN: 41558

American (AMR) AF: 0.000915 AC: 14 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00155 Hom.: 6

Bravo AF: 0.00440

ESP6500AA AF: 0.00886 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00125 AC: 152

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.57
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.87	N
REVEL	Benign	0.068
Sift	Benign	0.64	T
Sift4G	Benign	0.69	T
Polyphen		0.0040	B
Vest4		0.17
MutPred		0.20		Gain of phosphorylation at R944 (P = 0.0148)
MVP		0.45
MPC		0.017
ClinPred		0.0014	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.10
gMVP		0.15
Mutation Taster		=95/5	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: rs79685648; hg19: chr15-89843559; COSMIC: COSV104595277;