chr9-35074489-G-C

Variant names:

• chr9-35074489-G-C
• rs779834525
• NM_004629.2:c.1642C>G
• FANCG p.Arg548Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM1PM2BP4_Moderate

The NM_004629.2(FANCG):c.1642C>G (p.Arg548Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,148 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000609. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R548P: Uncertain_significance (ClinVar VariationId 4022545, 1 star); p.R548Q: Uncertain_significance (ClinVar VariationId 1692835, 1 star)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (1 hom.)
• Consequence: FANCG NM_004629.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.22
• Publications: 3 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 2 benign (OR vs. background: 5.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000609 — very rare for AR gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

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>G p.Arg548Gly	missense	Exon 13 of 14	Prot: NP_004620.1 UniProt:

FANCG NM_004629.2

MANE Select

HGVSc / HGVSpc.1642C>Gp.Arg548Gly

Exon rankExon 13 of 14

missense

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>G p.Arg548Gly	missense	Exon 13 of 14	Prot: ENSP00000367910.4 UniProt:
	FANCG ENST00000425676.5	TSL:1	n.*1118C>G	3_prime_UTR	Exon 12 of 13	Prot: ENSP00000412793.1 UniProt:
	FANCG ENST00000425676.5	TSL:1	n.*1118C>G	non_coding_transcript_exon	Exon 12 of 13	Prot: ENSP00000412793.1 UniProt:

FANCG ENST00000378643.8

TSL:1MANE Select

HGVSc / HGVSpc.1642C>Gp.Arg548Gly

Exon rankExon 13 of 14

missense

Prot: ENSP00000367910.4UniProt: O15287

FANCG ENST00000425676.5

TSL:1

HGVSc / HGVSpn.*1118C>G

Exon rankExon 12 of 13

3_prime_UTR

Prot: ENSP00000412793.1UniProt: F8WC08

FANCG ENST00000425676.5

TSL:1

HGVSc / HGVSpn.*1118C>G

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152148	Cov:32
GnomAD4 exome Warning	AF: 0.00000205	AC:3	Hom:1	AN:1461706	Cov:32
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152148	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:139360	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)
-	1	-	Fanconi anemia complementation group G (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	18
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.47	N
FuncVEP CTI	Benign	0.0091
GPN-Star LLR	N/A	-2.3
GPN-Star score	N/A	2.3
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	94/6	polymorphism
MutationAssessor	Benign	1.5	L
PhyloP100	Benign	2.2
popEVE	Benign	-3.5
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.046
Sift	Benign	0.12	T
Sift4G	Benign	0.069	T
Varity_R	N/A	0.10
VESM-3B	Benign	-6.3

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar