rs114549781

Variant names:

• chr15-89315330-A-G
• rs114549781
• NM_001113378.2:c.3865A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001113378.2(FANCI):​c.3865A>G​(p.Ile1289Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: FANCI NM_001113378.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.87
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028419763).
• BP6: Variant 15-89315330-A-G is Benign according to our data. Variant chr15-89315330-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 456219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00143 (218/152260) while in subpopulation AFR AF = 0.00469 (195/41540). AF 95% confidence interval is 0.00416. There are 1 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.3865A>G	p.Ile1289Val	missense	Exon 37 of 38	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.3865A>G	p.Ile1289Val	missense	Exon 37 of 38	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.3685A>G	p.Ile1229Val	missense	Exon 36 of 37	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.3865A>G	p.Ile1289Val	missense	Exon 37 of 38	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.3997A>G	p.Ile1333Val	missense	Exon 38 of 39	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.3889A>G	p.Ile1297Val	missense	Exon 37 of 38	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152142 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000350 AC: 88 AN: 251470 AF XY: 0.000250

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461790 Hom.: 0 Cov.: 30 AF XY: 0.000135 AC XY: 98 AN XY: 727202

African (AFR) AF: 0.00421 AC: 141 AN: 33470

American (AMR) AF: 0.000537 AC: 24 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111924

Other (OTH) AF: 0.000265 AC: 16 AN: 60392

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152260 Hom.: 1 Cov.: 31 AF XY: 0.00132 AC XY: 98 AN XY: 74466

African (AFR) AF: 0.00469 AC: 195 AN: 41540

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000447 Hom.: 1

Bravo AF: 0.00157

ESP6500AA AF: 0.00523 AC: 23

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia (2)
-	-	1	FANCI-related disorder (1)
-	-	1	Fanconi anemia complementation group I (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		8.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.84	N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.97
MPC		0.12
ClinPred		0.053	T
GERP RS		5.8
Varity_R		0.69
gMVP		0.36
Mutation Taster		=87/13	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: rs114549781; hg19: chr15-89858561;