rs878854178

Variant names:

• chr15-89305414-G-GT
• rs878854178
• NM_001113378.2:c.3255+6dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001113378.2(FANCI):​c.3255+6dupT variant causes a splice 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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 NM_001113378.2 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.45
• Publications: 0 publications found

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]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

LOC124903548 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	NM_001113378.2	MANE Select	c.3255+6dupT		splice_region intron	N/A	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.3255+6dupT		splice_region intron	N/A	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.3075+6dupT		splice_region intron	N/A	NP_060663.2	Q9NVI1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.3255+5_3255+6insT		splice_region intron	N/A	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.3255+5_3255+6insT		splice_region intron	N/A	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.3279+5_3279+6insT		splice_region intron	N/A	ENSP00000610873.1

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

GnomAD2 exomes AF: 0.00422 AC: 1060 AN: 251002 AF XY: 0.00422

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 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

African (AFR) AF: 0.000329 AC: 11 AN: 33460

American (AMR) AF: 0.000514 AC: 23 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.0145 AC: 577 AN: 39700

South Asian (SAS) AF: 0.00558 AC: 481 AN: 86220

European-Finnish (FIN) AF: 0.0240 AC: 1284 AN: 53418

Middle Eastern (MID) AF: 0.0112 AC: 58 AN: 5180

European-Non Finnish (NFE) AF: 0.000330 AC: 367 AN: 1111938

Other (OTH) AF: 0.00247 AC: 149 AN: 60308

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

African (AFR) AF: 0.0000721 AC: 3 AN: 41586

American (AMR) AF: 0.00150 AC: 23 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0152 AC: 79 AN: 5184

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4824

European-Finnish (FIN) AF: 0.0233 AC: 247 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs878854178; hg19: chr15-89848645; COSMIC: COSV104536575;