rs878854178

Positions:

• chr15-89305414-G-GT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000310775.12(FANCI):​c.3255+6dup variant causes a splice donor region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,398 control chromosomes in the GnomAD database, including 34 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (26 hom.)
• Consequence: FANCI ENST00000310775.12 splice_donor_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.45

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 -16 ACMG points.

• BP6: Variant 15-89305414-G-GT is Benign according to our data. Variant chr15-89305414-G-GT is described in ClinVar as [Likely_benign]. Clinvar id is 238322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0027 (412/152322) while in subpopulation EAS AF= 0.0152 (79/5184). AF 95% confidence interval is 0.0125. There are 8 homozygotes in gnomad4. There are 277 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCI	NM_001113378.2	c.3255+6dup		splice_donor_region_variant, intron_variant		ENST00000310775.12	NP_001106849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCI	ENST00000310775.12	c.3255+6dup		splice_donor_region_variant, intron_variant		1	NM_001113378.2	ENSP00000310842	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152204 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0152

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00422 AC: 1060 AN: 251002 Hom.: 8 AF XY: 0.00422 AC XY: 573 AN XY: 135808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0141

Gnomad SAS exome AF: 0.00529

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00203 AC: 2965 AN: 1461076 Hom.: 26 Cov.: 32 AF XY: 0.00215 AC XY: 1562 AN XY: 726844

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0145

Gnomad4 SAS exome AF: 0.00558

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00270 AC: 412 AN: 152322 Hom.: 8 Cov.: 32 AF XY: 0.00372 AC XY: 277 AN XY: 74480

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0152

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.00116

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.00101

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	FANCI: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 16, 2018

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs878854178; hg19: chr15-89848645;