9-35074487-TCG-GCC

Variant names:

• chr9-35074487-TCG-GCC
• NM_004629.2:c.1642_1644delCGAinsGGC
• FANCG p.Arg548Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM1PM2

The NM_004629.2(FANCG):c.1642_1644delCGAinsGGC (p.Arg548Gly) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R548G: Uncertain_significance (ClinVar VariationId 2062731, 2 stars); p.R548P: Uncertain_significance (ClinVar VariationId 4022545, 1 star); p.R548Q: Uncertain_significance (ClinVar VariationId 1692835, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCG NM_004629.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 0 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 4 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		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 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.1642_1644delCGAinsGGC p.Arg548Gly	missense	N/A	Prot: NP_004620.1 UniProt:

FANCG NM_004629.2

MANE Select

HGVSc / HGVSpc.1642_1644delCGAinsGGCp.Arg548Gly

Exon rankN/A

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.1642_1644delCGAinsGGC p.Arg548Gly	missense	N/A	Prot: ENSP00000367910.4 UniProt:
	FANCG ENST00000425676.5	TSL:1	n.*1118_*1120delCGAinsGGC	3_prime_UTR	Exon 12 of 13	Prot: ENSP00000412793.1 UniProt:
	FANCG ENST00000425676.5	TSL:1	n.*1118_*1120delCGAinsGGC	non_coding_transcript_exon	Exon 12 of 13	Prot: ENSP00000412793.1 UniProt:

FANCG ENST00000378643.8

TSL:1MANE Select

HGVSc / HGVSpc.1642_1644delCGAinsGGCp.Arg548Gly

Exon rankN/A

missense

Prot: ENSP00000367910.4UniProt: O15287

FANCG ENST00000425676.5

TSL:1

HGVSc / HGVSpn.*1118_*1120delCGAinsGGC

Exon rankExon 12 of 13

3_prime_UTR

Prot: ENSP00000412793.1UniProt: F8WC08

FANCG ENST00000425676.5

TSL:1

HGVSc / HGVSpn.*1118_*1120delCGAinsGGC

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr9-35074484;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar