9-35075318-C-T

Variant names:

• chr9-35075318-C-T
• rs772460728
• NM_004629.2:c.1441G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004629.2(FANCG):​c.1441G>A​(p.Glu481Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E481Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FANCG NM_004629.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• 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, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCG	NM_004629.2	MANE Select	c.1441G>A	p.Glu481Lys	missense	Exon 11 of 14	NP_004620.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCG	ENST00000378643.8	TSL:1 MANE Select	c.1441G>A	p.Glu481Lys	missense	Exon 11 of 14	ENSP00000367910.4
	FANCG	ENST00000425676.5	TSL:1	n.*917G>A		non_coding_transcript_exon	Exon 10 of 13	ENSP00000412793.1
	FANCG	ENST00000425676.5	TSL:1	n.*917G>A		3_prime_UTR	Exon 10 of 13	ENSP00000412793.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461866 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74246

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Benign	0.072	T
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.44		Gain of MoRF binding (P = 0.0105)
MVP		0.63
MPC		0.86
ClinPred		0.85	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.32
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs772460728; hg19: chr9-35075315; COSMIC: COSV62719596; COSMIC: COSV62719596;