15-89315371-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001113378.2(FANCI):c.3906T>C(p.Gly1302=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,610,096 control chromosomes in the GnomAD database, including 129,487 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13320 hom., cov: 31)
  • Exomes 𝑓: 0.40 (116167 hom.)
• Consequence: FANCI NM_001113378.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.907

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]

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-89315371-T-C is Benign according to our data. Variant chr15-89315371-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.907 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCI	NM_001113378.2	c.3906T>C	p.Gly1302=	synonymous_variant	37/38	ENST00000310775.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCI	ENST00000310775.12	c.3906T>C	p.Gly1302=	synonymous_variant	37/38	1	NM_001113378.2	P1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63213 AN: 151730 Hom.: 13306 Cov.: 31

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.362

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.398

GnomAD3 exomes AF: 0.410 AC: 102944 AN: 251360 Hom.: 21395 AF XY: 0.410 AC XY: 55729 AN XY: 135864

Gnomad AFR exome AF: 0.440

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.428

Gnomad SAS exome AF: 0.406

Gnomad FIN exome AF: 0.503

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.397 AC: 579240 AN: 1458248 Hom.: 116167 Cov.: 31 AF XY: 0.398 AC XY: 288469 AN XY: 725584

Gnomad4 AFR exome AF: 0.445

Gnomad4 AMR exome AF: 0.387

Gnomad4 ASJ exome AF: 0.393

Gnomad4 EAS exome AF: 0.411

Gnomad4 SAS exome AF: 0.407

Gnomad4 FIN exome AF: 0.495

Gnomad4 NFE exome AF: 0.390

Gnomad4 OTH exome AF: 0.405

GnomAD4 genome AF: 0.417 AC: 63259 AN: 151848 Hom.: 13320 Cov.: 31 AF XY: 0.424 AC XY: 31477 AN XY: 74210

Gnomad4 AFR AF: 0.445

Gnomad4 AMR AF: 0.373

Gnomad4 ASJ AF: 0.378

Gnomad4 EAS AF: 0.434

Gnomad4 SAS AF: 0.402

Gnomad4 FIN AF: 0.510

Gnomad4 NFE AF: 0.398

Gnomad4 OTH AF: 0.394

Alfa AF: 0.394 Hom.: 19580

Bravo AF: 0.409

Asia WGS AF: 0.400 AC: 1389 AN: 3478

EpiCase AF: 0.387

EpiControl AF: 0.390

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group I Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

POLG-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.31
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1138465; hg19: chr15-89858602; COSMIC: COSV51519356; COSMIC: COSV51519356;