rs139814895

Variant names:

• chr15-89292706-A-G
• rs139814895
• NM_001113378.2:c.2011A>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.2011A>G​(p.Ile671Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,706 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I671F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (28 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.06
• Publications: 9 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=0.0055571496).
• BP6: Variant 15-89292706-A-G is Benign according to our data. Variant chr15-89292706-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00271 (412/152286) while in subpopulation EAS AF = 0.0148 (77/5190). AF 95% confidence interval is 0.0122. There are 8 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.2011A>G	p.Ile671Val	missense	Exon 21 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.2011A>G	p.Ile671Val	missense	Exon 21 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.2011A>G	p.Ile671Val	missense	Exon 21 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.2011A>G	p.Ile671Val	missense	Exon 21 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.2011A>G	p.Ile671Val	missense	Exon 21 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.2011A>G	p.Ile671Val	missense	Exon 21 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152168 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00424 AC: 1053 AN: 248556 AF XY: 0.00428

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0137

Gnomad FIN exome AF: 0.0240

Gnomad NFE exome AF: 0.000702

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00205 AC: 2999 AN: 1461420 Hom.: 28 Cov.: 32 AF XY: 0.00217 AC XY: 1579 AN XY: 727028

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26132

East Asian (EAS) AF: 0.0144 AC: 573 AN: 39668

South Asian (SAS) AF: 0.00586 AC: 505 AN: 86248

European-Finnish (FIN) AF: 0.0239 AC: 1271 AN: 53106

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5768

European-Non Finnish (NFE) AF: 0.000331 AC: 368 AN: 1111908

Other (OTH) AF: 0.00248 AC: 150 AN: 60386

GnomAD4 genome AF: 0.00271 AC: 412 AN: 152286 Hom.: 8 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74462

African (AFR) AF: 0.0000722 AC: 3 AN: 41552

American (AMR) AF: 0.00150 AC: 23 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0148 AC: 77 AN: 5190

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4824

European-Finnish (FIN) AF: 0.0233 AC: 247 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00119 Hom.: 4

Bravo AF: 0.00117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00393 AC: 477

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00101

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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.1
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.023
Sift	Benign	0.12	T
Sift4G	Benign	0.39	T
Polyphen		0.0050	B
Vest4		0.14
MVP		0.27
MPC		0.016
ClinPred		0.019	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.14
Mutation Taster		=98/2	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: rs139814895; hg19: chr15-89835937; COSMIC: COSV55524716; COSMIC: COSV55524716;