rs4779794

Positions:

• chr15-30905361-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:4
• Conservation: PhyloP100: -0.298

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 260492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-30905361-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAN1	NM_014967.5	c.698G>A	p.Gly233Glu	missense_variant	2/15	ENST00000362065.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAN1	ENST00000362065.9	c.698G>A	p.Gly233Glu	missense_variant	2/15	1	NM_014967.5	P1

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

GnomAD3 exomes AF: 0.470 AC: 118017 AN: 251040 Hom.: 30343 AF XY: 0.471 AC XY: 63890 AN XY: 135732

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 SAS exome AF: 0.511

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

Gnomad4 AFR exome AF: 0.0916

Gnomad4 AMR exome AF: 0.557

Gnomad4 ASJ exome AF: 0.479

Gnomad4 EAS exome AF: 0.802

Gnomad4 SAS exome AF: 0.511

Gnomad4 FIN exome AF: 0.465

Gnomad4 NFE exome AF: 0.430

Gnomad4 OTH exome AF: 0.439

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

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.501

Gnomad4 EAS AF: 0.797

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.427

Gnomad4 OTH AF: 0.382

Alfa AF: 0.427 Hom.: 31048

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Karyomegalic interstitial nephritis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;.;T
MetaRNN	Benign	0.0000013	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M;M;M;M
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.070	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.79	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.42	B;B;B;B
Vest4		0.037
MPC		0.20
ClinPred		0.0079	T
GERP RS		-2.2
Varity_R		0.030
gMVP		0.072

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

Publications

LitVar

Other links and lift over

dbSNP: rs4779794; hg19: chr15-31197564; COSMIC: COSV62949927;