chr15-30929225-CA-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_014967.5(FAN1):c.2616delA(p.Asp873ThrfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,612,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

FAN1
NM_014967.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -3.60

Publications

4 publications found

Variant links:

Genes affected

FAN1 (HGNC:29170): (FANCD2 and FANCI associated nuclease 1) This gene plays a role in DNA interstrand cross-link repair and encodes a protein with 5' flap endonuclease and 5'-3' exonuclease activity. Mutations in this gene cause karyomegalic interstitial nephritis. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Feb 2016]

FAN1 links:

MTMR10 (HGNC:25999): (myotubularin related protein 10) Predicted to enable phosphatidylinositol-3-phosphatase activity. Predicted to be involved in phosphatidylinositol dephosphorylation. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MTMR10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 15-30929225-CA-C is Pathogenic according to our data. Variant chr15-30929225-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 437429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAN1	NM_014967.5 link	c.2616delA	p.Asp873ThrfsTer17	frameshift_variant	Exon 12 of 15	ENST00000362065.9	NP_055782.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAN1	ENST00000362065.9 link	c.2616delA	p.Asp873ThrfsTer17	frameshift_variant	Exon 12 of 15	1	NM_014967.5	ENSP00000354497.4

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000922

AC:

AN:

249482

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1460460

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

726600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33384

American (AMR)

AF:

0.00

AC:

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.000477

AC:

AN:

86014

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111470

Other (OTH)

AF:

0.0000497

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Karyomegalic interstitial nephritis

Pathogenic:4

Oct 09, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous frameshift deletion variant, NM_014967.4(FAN1):c.2616delA, has been identified in exon 12 of 15 of the FAN1 gene. This deletion is predicted to create a frameshift starting at amino acid position 873, introducing a stop codon 17 residues downstream (NP_055782.3(FAN1):p.(Asp873Thrfs*17)). This variant is predicted to result in loss of protein function through nonsense mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.01% (25 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in two patients with chronic kidney disease (ClinVar, Zhou, W. et al (2012)). Other upstream LoF variants have also been reported as pathogenic (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

Jul 08, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 21, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FAN1: PVS1, PM2, PM3, PP1:Moderate

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Asp873Thrfs*17) in the FAN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FAN1 are known to be pathogenic (PMID: 22772369). This variant is present in population databases (rs750056424, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with interstitial nephritis (PMID: 22772369, 27196444, 32220227). ClinVar contains an entry for this variant (Variation ID: 437429). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-3.6

Mutation Taster

=4/196

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over