NM_001113378.2:c.158G>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2PP3_StrongBP6

The NM_001113378.2(FANCI):c.158G>C(p.Gly53Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000237 in 1,613,354 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G53V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

FANCI
NM_001113378.2 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 6.56

Publications

8 publications found

Variant links:

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

FANCI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 15-89260713-G-C is Benign according to our data. Variant chr15-89260713-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408254.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCI	NM_001113378.2	MANE Select	c.158G>C	p.Gly53Ala	missense splice_region	Exon 4 of 38	NP_001106849.1
FANCI	NM_001376911.1		c.158G>C	p.Gly53Ala	missense splice_region	Exon 4 of 38	NP_001363840.1
FANCI	NM_018193.3		c.158G>C	p.Gly53Ala	missense splice_region	Exon 4 of 37	NP_060663.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCI	ENST00000310775.12	TSL:1 MANE Select	c.158G>C	p.Gly53Ala	missense splice_region	Exon 4 of 38	ENSP00000310842.8
FANCI	ENST00000567996.5	TSL:1	c.158G>C	p.Gly53Ala	missense splice_region	Exon 6 of 11	ENSP00000458024.1
FANCI	ENST00000674831.1		c.158G>C	p.Gly53Ala	missense splice_region	Exon 4 of 39	ENSP00000502474.1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000453

AC:

114

AN:

251444

AF XY:

0.000530

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000233

AC:

341

AN:

1461282

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

185

AN XY:

726966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

268

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111668

Other (OTH)

AF:

0.000613

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000276

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000735

Hom.:

Bravo

AF:

0.000298

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia

Benign:2

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 25, 2020

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Fanconi anemia complementation group I

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

not specified

Benign:1

Jun 10, 2022

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.011

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.7

PhyloP100

6.6

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.90

REVEL

Uncertain

0.54

Sift

Benign

0.22

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.74

MVP

0.99

MPC

0.073

ClinPred

0.12

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.48

Mutation Taster

=191/109

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.39

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over