NM_014967.5:c.1520G>A

Variant names:

• chr15-30910758-G-A
• rs150393409
• NM_014967.5:c.1520G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014967.5(FAN1):​c.1520G>A​(p.Arg507His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0089 in 1,614,058 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R507P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (82 hom.)
• Consequence: FAN1 NM_014967.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.43
• Publications: 30 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008552343).
• BP6: Variant 15-30910758-G-A is Benign according to our data. Variant chr15-30910758-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 619975.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00604 (920/152208) while in subpopulation NFE AF = 0.0099 (673/68004). AF 95% confidence interval is 0.00928. There are 4 homozygotes in GnomAd4. There are 404 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAN1	NM_014967.5	MANE Select	c.1520G>A	p.Arg507His	missense	Exon 4 of 15	NP_055782.3	Q9Y2M0-1
	FAN1	NM_001146094.2		c.1520G>A	p.Arg507His	missense	Exon 4 of 4	NP_001139566.1	Q9Y2M0-2
	FAN1	NM_001146095.1		c.1520G>A	p.Arg507His	missense	Exon 4 of 4	NP_001139567.1	Q9Y2M0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAN1	ENST00000362065.9	TSL:1 MANE Select	c.1520G>A	p.Arg507His	missense	Exon 4 of 15	ENSP00000354497.4	Q9Y2M0-1
	FAN1	ENST00000561594.5	TSL:1	c.1520G>A	p.Arg507His	missense	Exon 4 of 4	ENSP00000455983.1	Q9Y2M0-2
	FAN1	ENST00000561607.6	TSL:1	c.1520G>A	p.Arg507His	missense	Exon 4 of 4	ENSP00000454223.1	Q9Y2M0-2

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 920 AN: 152090 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00990

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00656 AC: 1649 AN: 251456 AF XY: 0.00684

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00430

Gnomad NFE exome AF: 0.00964

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00920 AC: 13449 AN: 1461850 Hom.: 82 Cov.: 32 AF XY: 0.00906 AC XY: 6589 AN XY: 727228

African (AFR) AF: 0.00164 AC: 55 AN: 33480

American (AMR) AF: 0.00476 AC: 213 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 274 AN: 26136

East Asian (EAS) AF: 0.00146 AC: 58 AN: 39696

South Asian (SAS) AF: 0.00348 AC: 300 AN: 86258

European-Finnish (FIN) AF: 0.00444 AC: 237 AN: 53420

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.0106 AC: 11817 AN: 1111980

Other (OTH) AF: 0.00772 AC: 466 AN: 60390

GnomAD4 genome AF: 0.00604 AC: 920 AN: 152208 Hom.: 4 Cov.: 33 AF XY: 0.00543 AC XY: 404 AN XY: 74412

African (AFR) AF: 0.00154 AC: 64 AN: 41516

American (AMR) AF: 0.00458 AC: 70 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00538 AC: 57 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00990 AC: 673 AN: 68004

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00780 Hom.: 9

Bravo AF: 0.00624

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00619 AC: 751

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00965

EpiControl AF: 0.0119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Karyomegalic interstitial nephritis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.11
Sift	Benign	0.030	D
Sift4G	Uncertain	0.048	D
Polyphen		0.91	P
Vest4		0.15
MVP		0.43
MPC		0.47
ClinPred		0.019	T
GERP RS		2.6
Varity_R		0.21
gMVP		0.25
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: rs150393409; hg19: chr15-31202961; COSMIC: COSV100755790; COSMIC: COSV100755790;