rs187082481

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_014967.5(FAN1):c.1090A>C(p.Asn364His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

FAN1
NM_014967.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.207

Publications

0 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 Gene-Disease associations (from GenCC):

karyomegalic interstitial nephritis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
Lynch syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

FAN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031412244).

BP6

Variant 15-30905753-A-C is Benign according to our data. Variant chr15-30905753-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373299.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00019 (278/1461892) while in subpopulation AMR AF = 0.00604 (270/44724). AF 95% confidence interval is 0.00545. There are 0 homozygotes in GnomAdExome4. There are 122 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014967.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAN1	NM_014967.5	MANE Select	c.1090A>C	p.Asn364His	missense	Exon 2 of 15	NP_055782.3	Q9Y2M0-1
FAN1	NM_001146094.2		c.1090A>C	p.Asn364His	missense	Exon 2 of 4	NP_001139566.1	Q9Y2M0-2
FAN1	NM_001146095.1		c.1090A>C	p.Asn364His	missense	Exon 2 of 4	NP_001139567.1	Q9Y2M0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAN1	ENST00000362065.9	TSL:1 MANE Select	c.1090A>C	p.Asn364His	missense	Exon 2 of 15	ENSP00000354497.4	Q9Y2M0-1
FAN1	ENST00000561594.5	TSL:1	c.1090A>C	p.Asn364His	missense	Exon 2 of 4	ENSP00000455983.1	Q9Y2M0-2
FAN1	ENST00000561607.6	TSL:1	c.1090A>C	p.Asn364His	missense	Exon 2 of 4	ENSP00000454223.1	Q9Y2M0-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00101

AC:

253

AN:

251448

AF XY:

0.000802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000190

AC:

278

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00604

AC:

270

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.000116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

104

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:

0.000125

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41562

American (AMR)

AF:

0.00118

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.0000611

Hom.:

Bravo

AF:

0.000351

ExAC

AF:

0.000914

AC:

111

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

FAN1-related disorder (1)

Karyomegalic interstitial nephritis (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

3.0

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0049

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.63

M_CAP

Benign

0.0098

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

0.21

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.80

REVEL

Benign

0.030

Sift

Benign

0.18

Sift4G

Benign

0.24

Polyphen

0.85

Vest4

0.089

MVP

0.23

MPC

0.099

ClinPred

0.028

GERP RS

1.8

Varity_R

0.045

gMVP

0.17

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over