chr15-89295005-A-C

Variant names:

• chr15-89295005-A-C
• rs7183618
• NM_001113378.2:c.2547A>C

Variant summary

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

The NM_001113378.2(FANCI):​c.2547A>C​(p.Lys849Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K849K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 25 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2547A>C	p.Lys849Asn	missense	Exon 24 of 38	NP_001106849.1
	FANCI	NM_001376911.1		c.2547A>C	p.Lys849Asn	missense	Exon 24 of 38	NP_001363840.1
	FANCI	NM_001376910.1		c.2268A>C	p.Lys756Asn	missense	Exon 24 of 38	NP_001363839.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.2547A>C	p.Lys849Asn	missense	Exon 24 of 38	ENSP00000310842.8
	FANCI	ENST00000674831.1		c.2547A>C	p.Lys849Asn	missense	Exon 24 of 39	ENSP00000502474.1
	FANCI	ENST00000696719.1		c.2547A>C	p.Lys849Asn	missense	Exon 25 of 39	ENSP00000512832.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DEOGEN2	Benign	0.20	T
LIST_S2	Uncertain	0.92	D
MetaRNN	Uncertain	0.73	D
PhyloP100		1.7
PROVEAN	Benign	-2.3	N
Sift	Benign	0.20	T
Sift4G	Pathogenic	0.0	D
Vest4		0.77
gMVP		0.63

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: rs7183618; hg19: chr15-89838236;