rs4779794

Variant names:

• chr15-30905361-G-A
• rs4779794
• NM_014967.5:c.698G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014967.5(FAN1):​c.698G>A​(p.Gly233Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,613,248 control chromosomes in the GnomAD database, including 162,354 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G233V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.37 (12527 hom., cov: 32)
  • Exomes 𝑓: 0.44 (149827 hom.)
• Consequence: FAN1 NM_014967.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.298
• Publications: 51 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2572472E-6).
• BP6: Variant 15-30905361-G-A is Benign according to our data. Variant chr15-30905361-G-A is described in ClinVar as Benign. ClinVar VariationId is 260492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

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.698G>A	p.Gly233Glu	missense	Exon 2 of 15	NP_055782.3	Q9Y2M0-1
	FAN1	NM_001146094.2		c.698G>A	p.Gly233Glu	missense	Exon 2 of 4	NP_001139566.1	Q9Y2M0-2
	FAN1	NM_001146095.1		c.698G>A	p.Gly233Glu	missense	Exon 2 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.698G>A	p.Gly233Glu	missense	Exon 2 of 15	ENSP00000354497.4	Q9Y2M0-1
	FAN1	ENST00000561594.5	TSL:1	c.698G>A	p.Gly233Glu	missense	Exon 2 of 4	ENSP00000455983.1	Q9Y2M0-2
	FAN1	ENST00000561607.6	TSL:1	c.698G>A	p.Gly233Glu	missense	Exon 2 of 4	ENSP00000454223.1	Q9Y2M0-2

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55737 AN: 151924 Hom.: 12515 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.470 AC: 118017 AN: 251040 AF XY: 0.471

Gnomad AFR exome AF: 0.0992

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.804

Gnomad FIN exome AF: 0.466

Gnomad NFE exome AF: 0.428

Gnomad OTH exome AF: 0.470

GnomAD4 exome AF: 0.443 AC: 647721 AN: 1461206 Hom.: 149827 Cov.: 37 AF XY: 0.445 AC XY: 323303 AN XY: 726916

African (AFR) AF: 0.0916 AC: 3064 AN: 33468

American (AMR) AF: 0.557 AC: 24890 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 12526 AN: 26124

East Asian (EAS) AF: 0.802 AC: 31839 AN: 39690

South Asian (SAS) AF: 0.511 AC: 44060 AN: 86246

European-Finnish (FIN) AF: 0.465 AC: 24774 AN: 53310

Middle Eastern (MID) AF: 0.407 AC: 2350 AN: 5768

European-Non Finnish (NFE) AF: 0.430 AC: 477691 AN: 1111534

Other (OTH) AF: 0.439 AC: 26527 AN: 60372

GnomAD4 genome AF: 0.367 AC: 55752 AN: 152042 Hom.: 12527 Cov.: 32 AF XY: 0.379 AC XY: 28153 AN XY: 74312

African (AFR) AF: 0.111 AC: 4596 AN: 41500

American (AMR) AF: 0.484 AC: 7399 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1737 AN: 3464

East Asian (EAS) AF: 0.797 AC: 4113 AN: 5162

South Asian (SAS) AF: 0.534 AC: 2580 AN: 4828

European-Finnish (FIN) AF: 0.468 AC: 4939 AN: 10558

Middle Eastern (MID) AF: 0.442 AC: 129 AN: 292

European-Non Finnish (NFE) AF: 0.427 AC: 29022 AN: 67946

Other (OTH) AF: 0.382 AC: 807 AN: 2110

Alfa AF: 0.412 Hom.: 48000

Bravo AF: 0.358

TwinsUK AF: 0.438 AC: 1624

ALSPAC AF: 0.444 AC: 1711

ESP6500AA AF: 0.112 AC: 494

ESP6500EA AF: 0.426 AC: 3661

ExAC AF: 0.459 AC: 55717

Asia WGS AF: 0.607 AC: 2109 AN: 3478

EpiCase AF: 0.426

EpiControl AF: 0.429

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Karyomegalic interstitial nephritis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.74
DANN	Benign	0.39
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.30
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.033
Sift	Benign	0.79	T
Sift4G	Benign	0.71	T
Polyphen		0.42	B
Vest4		0.037
MPC		0.20
ClinPred		0.0079	T
GERP RS		-2.2
Varity_R		0.030
gMVP		0.072
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs4779794; hg19: chr15-31197564; COSMIC: COSV62949927;