NM_001113378.2:c.1491A>C

Variant names:

• chr15-89281279-A-C
• rs145349375
• NM_001113378.2:c.1491A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001113378.2(FANCI):​c.1491A>C​(p.Gln497His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. Q497K) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1869205).

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.1491A>C	p.Gln497His	missense	Exon 15 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.1491A>C	p.Gln497His	missense	Exon 15 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.1491A>C	p.Gln497His	missense	Exon 15 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.1491A>C	p.Gln497His	missense	Exon 15 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.1491A>C	p.Gln497His	missense	Exon 15 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.1491A>C	p.Gln497His	missense	Exon 15 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74372

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	9.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.0020
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.42
Sift	Benign	0.19	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.14	B
Vest4		0.29
MutPred		0.24		Loss of MoRF binding (P = 0.1528)
MVP		0.78
MPC		0.016
ClinPred		0.18	T
GERP RS		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.43
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs145349375; hg19: chr15-89824510;