9-35078285-C-T

Variant names:

• chr9-35078285-C-T
• rs546023787
• NM_004629.2:c.366G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004629.2(FANCG):​c.366G>A​(p.Trp122*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCG NM_004629.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.16
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35078285-C-T is Pathogenic according to our data. Variant chr9-35078285-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2675575.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCG	NM_004629.2	MANE Select	c.366G>A	p.Trp122*	stop_gained	Exon 4 of 14	NP_004620.1	O15287

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCG	ENST00000378643.8	TSL:1 MANE Select	c.366G>A	p.Trp122*	stop_gained	Exon 4 of 14	ENSP00000367910.4	O15287
	FANCG	ENST00000425676.5	TSL:1	n.307+320G>A		intron	N/A	ENSP00000412793.1	F8WC08
	FANCG	ENST00000448890.2	TSL:3	c.366G>A	p.Trp122*	stop_gained	Exon 5 of 15	ENSP00000409607.2	O15287

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		4.2
Vest4		0.79
GERP RS		5.5
Mutation Taster		=11/189	disease causing (fs/PTC)

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: rs546023787; hg19: chr9-35078282;