chr15-89307605-T-C

Position:

chr15-89307605-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001113378.2(FANCI):c.3592-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,216 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 10 hom. )

Consequence

FANCI
NM_001113378.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.000006081

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.230

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 links:

POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

POLG links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 15-89307605-T-C is Benign according to our data. Variant chr15-89307605-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 238326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89307605-T-C is described in Lovd as [Benign]. Variant chr15-89307605-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (292/152326) while in subpopulation NFE AF= 0.0034 (231/68034). AF 95% confidence interval is 0.00304. There are 1 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCI	NM_001113378.2 linkuse as main transcript	c.3592-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000310775.12	NP_001106849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCI	ENST00000310775.12 linkuse as main transcript	c.3592-8T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001113378.2	ENSP00000310842	P1	Q9NVI1-3

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

292

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00339

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00226

AC:

568

AN:

251478

Hom.:

AF XY:

0.00232

AC XY:

316

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00245

Gnomad NFE exome

AF:

0.00420

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00286

AC:

4181

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00275

AC XY:

1999

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00198

Gnomad4 NFE exome

AF:

0.00352

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00192

AC:

292

AN:

152326

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00340

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00291

Hom.:

Bravo

AF:

0.00201

EpiCase

AF:

0.00311

EpiControl

AF:

0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 29, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FANCI: BP4, BS2 -

Fanconi anemia complementation group I

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Fanconi anemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 10, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.7

DANN

Benign

0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000061

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over