rs779834525

Variant names:

• chr9-35074489-G-A
• rs779834525
• NM_004629.2:c.1642C>T
• FANCG p.Arg548*

Your query was ambiguous. Multiple possible variants found:

• chr9-35074489-G-A
• chr9-35074489-G-C

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_004629.2(FANCG):c.1642C>T (p.Arg548*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000446 (AC=72) in the gnomAD database across 1,613,854 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000461. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: FANCG NM_004629.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.22
• Publications: 8 publications found

Genes affected

FANCG (HGNC:3588): (FA complementation group G) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group G. [provided by RefSeq, Jul 2008]

FANCG Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group G

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Natera
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 13 of 14) at amino acid 548 of 622, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000461 — very rare for AR gene (threshold 0.001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004629.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FANCG NM_004629.2	MANE Select	c.1642C>T p.Arg548*	stop_gained	Exon 13 of 14	Prot: NP_004620.1 UniProt:

FANCG NM_004629.2

MANE Select

HGVSc / HGVSpc.1642C>Tp.Arg548*

Exon rankExon 13 of 14

stop_gained

Prot: NP_004620.1UniProt: O15287Q53XM5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FANCG ENST00000378643.8	TSL:1MANE Select	c.1642C>T p.Arg548*	stop_gained	Exon 13 of 14	Prot: ENSP00000367910.4 UniProt:
	FANCG ENST00000425676.5	TSL:1	n.*1118C>T	3_prime_UTR	Exon 12 of 13	Prot: ENSP00000412793.1 UniProt:
	FANCG ENST00000425676.5	TSL:1	n.*1118C>T	non_coding_transcript_exon	Exon 12 of 13	Prot: ENSP00000412793.1 UniProt:

FANCG ENST00000378643.8

TSL:1MANE Select

HGVSc / HGVSpc.1642C>Tp.Arg548*

Exon rankExon 13 of 14

stop_gained

Prot: ENSP00000367910.4UniProt: O15287

FANCG ENST00000425676.5

TSL:1

HGVSc / HGVSpn.*1118C>T

Exon rankExon 12 of 13

3_prime_UTR

Prot: ENSP00000412793.1UniProt: F8WC08

FANCG ENST00000425676.5

TSL:1

HGVSc / HGVSpn.*1118C>T

Exon rankExon 12 of 13

non_coding_transcript_exon

Prot: ENSP00000412793.1UniProt: F8WC08

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152148	Cov:32
GnomAD2 exomes	AF: 0.0000200	AC:5	Hom:	AN:249540	Cov:
GnomAD4 exome	AF: 0.0000472	AC:69	Hom:0	AN:1461706	Cov:32
GnomAD4 genome	AF: 0.0000197	AC:3	Hom:0	AN:152148	Cov:32
TOPMed (Bravo)	AF: 0.0000340	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000718	AC:10	Hom:0	AN:139360	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000693	2	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000449	3	66884
SCHEMA(Schizophrenia)	0.0000268	3	111952	0.0000265	5	188700

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Fanconi anemia complementation group G (6)
2	-	-	Fanconi anemia (2)
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	38
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.45	N
GPN-Star LLR	N/A	-6.3
GPN-Star score	N/A	6.3
Mutation Taster	N/A	22/178	disease causing (ClinVar)
PhyloP100	Benign	2.2

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AL_spliceai	Uncertain	0.21	Position offset: 5
Pangolin (max)	Benign	0.20
Pangolin loss	Uncertain	0.20	Position offset: 5
SpliceAI score (max)	Uncertain	0.21	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs779834525;

hg19: chr9-35074486;

COSMIC: COSV62722335;

COSMIC: COSV62722335;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar