NM_001113378.2:c.257C>T

Variant names:

• chr15-89260812-C-T
• rs17803620
• NM_001113378.2:c.257C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001113378.2(FANCI):​c.257C>T​(p.Ala86Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,612,532 control chromosomes in the GnomAD database, including 112,025 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A86G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (8212 hom., cov: 32)
  • Exomes 𝑓: 0.37 (103813 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.06
• Publications: 51 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 -16 ACMG points.

• BP6: Variant 15-89260812-C-T is Benign according to our data. Variant chr15-89260812-C-T is described in ClinVar as Benign. ClinVar VariationId is 257484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

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.257C>T	p.Ala86Val	missense	Exon 4 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.257C>T	p.Ala86Val	missense	Exon 4 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.257C>T	p.Ala86Val	missense	Exon 4 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.257C>T	p.Ala86Val	missense	Exon 4 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000567996.5	TSL:1	c.257C>T	p.Ala86Val	missense	Exon 6 of 11	ENSP00000458024.1	Q9NVI1-4
	FANCI	ENST00000674831.1		c.257C>T	p.Ala86Val	missense	Exon 4 of 39	ENSP00000502474.1	A0A6Q8PH09

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45344 AN: 151798 Hom.: 8212 Cov.: 32

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.307

GnomAD2 exomes AF: 0.360 AC: 90634 AN: 251442 AF XY: 0.369

Gnomad AFR exome AF: 0.0801

Gnomad AMR exome AF: 0.362

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.319

Gnomad FIN exome AF: 0.460

Gnomad NFE exome AF: 0.380

Gnomad OTH exome AF: 0.363

GnomAD4 exome AF: 0.372 AC: 543699 AN: 1460616 Hom.: 103813 Cov.: 39 AF XY: 0.374 AC XY: 271711 AN XY: 726696

African (AFR) AF: 0.0734 AC: 2457 AN: 33466

American (AMR) AF: 0.355 AC: 15895 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 9963 AN: 26118

East Asian (EAS) AF: 0.306 AC: 12138 AN: 39654

South Asian (SAS) AF: 0.384 AC: 33098 AN: 86228

European-Finnish (FIN) AF: 0.454 AC: 24189 AN: 53334

Middle Eastern (MID) AF: 0.329 AC: 1897 AN: 5766

European-Non Finnish (NFE) AF: 0.380 AC: 422231 AN: 1110996

Other (OTH) AF: 0.362 AC: 21831 AN: 60340

GnomAD4 genome AF: 0.298 AC: 45337 AN: 151916 Hom.: 8212 Cov.: 32 AF XY: 0.306 AC XY: 22729 AN XY: 74218

African (AFR) AF: 0.0879 AC: 3645 AN: 41474

American (AMR) AF: 0.309 AC: 4716 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1279 AN: 3470

East Asian (EAS) AF: 0.318 AC: 1641 AN: 5164

South Asian (SAS) AF: 0.375 AC: 1803 AN: 4804

European-Finnish (FIN) AF: 0.469 AC: 4932 AN: 10510

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26233 AN: 67912

Other (OTH) AF: 0.305 AC: 644 AN: 2110

Alfa AF: 0.345 Hom.: 28945

Bravo AF: 0.281

TwinsUK AF: 0.370 AC: 1373

ALSPAC AF: 0.353 AC: 1361

ESP6500AA AF: 0.0948 AC: 417

ESP6500EA AF: 0.384 AC: 3304

ExAC AF: 0.357 AC: 43326

Asia WGS AF: 0.312 AC: 1083 AN: 3478

EpiCase AF: 0.375

EpiControl AF: 0.378

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group I (4)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.055
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.15
Sift	Benign	0.34	T
Sift4G	Benign	0.078	T
Polyphen		0.75	P
Vest4		0.13
MPC		0.019
ClinPred		0.014	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.30
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17803620; hg19: chr15-89804043; COSMIC: COSV55527083; COSMIC: COSV55527083;