chr15-89316836-T-C

Variant names:

• chr15-89316836-T-C
• rs115048121
• NM_001113378.2:c.*377T>C

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.*377T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,607,264 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (15 hom.)
• Consequence: FANCI NM_001113378.2 3_prime_UTR
• Scores: Splicing: ADA: 0.00006921
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.03

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-89316836-T-C is Benign according to our data. Variant chr15-89316836-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89316836-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00725 (1104/152280) while in subpopulation AFR AF = 0.0253 (1053/41540). AF 95% confidence interval is 0.0241. There are 16 homozygotes in GnomAd4. There are 543 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCI	NM_001113378.2	c.*377T>C		3_prime_UTR_variant	Exon 38 of 38	ENST00000310775.12	NP_001106849.1
POLG	NM_002693.3	c.3644-9A>G		intron_variant	Intron 22 of 22	ENST00000268124.11	NP_002684.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCI	ENST00000310775.12	c.*377T>C		3_prime_UTR_variant	Exon 38 of 38	1	NM_001113378.2	ENSP00000310842.8
POLG	ENST00000268124.11	c.3644-9A>G		intron_variant	Intron 22 of 22	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1101 AN: 152162 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00179 AC: 449 AN: 251238 AF XY: 0.00124

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000735 AC: 1069 AN: 1454984 Hom.: 15 Cov.: 29 AF XY: 0.000628 AC XY: 455 AN XY: 724412

Gnomad4 AFR exome AF: 0.0272 AC: 905 AN: 33312

Gnomad4 AMR exome AF: 0.00112 AC: 50 AN: 44712

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26104

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39668

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86122

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53414

Gnomad4 NFE exome AF: 0.0000244 AC: 27 AN: 1105748

Gnomad4 Remaining exome AF: 0.00136 AC: 82 AN: 60144

GnomAD4 genome AF: 0.00725 AC: 1104 AN: 152280 Hom.: 16 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74472

Gnomad4 AFR AF: 0.0253 AC: 0.0253491 AN: 0.0253491

Gnomad4 AMR AF: 0.00242 AC: 0.00241798 AN: 0.00241798

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207211 AN: 0.000207211

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294014 AN: 0.0000294014

Gnomad4 OTH AF: 0.00520 AC: 0.00520341 AN: 0.00520341

Alfa AF: 0.00663 Hom.: 10

Bravo AF: 0.00826

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Progressive sclerosing poliodystrophy Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2018

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_002693.2:c.3644-9A>G (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89316836T>C] variant in FANCI gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BA1:Minor allele frequency is too high for the Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the FANCI structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Benign. -

not provided Benign:1

May 21, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group I Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.0020
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: rs115048121; hg19: chr15-89860067;