9-35075734-AGGGGAGG-A

Variant names:

• chr9-35075734-AGGGGAGG-A
• rs1554670228
• NM_004629.2:c.1157_1163delCCTCCCC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004629.2(FANCG):​c.1157_1163delCCTCCCC​(p.Pro386LeufsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 484,984 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P386P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: FANCG NM_004629.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99
• 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, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCG	NM_004629.2	c.1157_1163delCCTCCCC	p.Pro386LeufsTer15	frameshift_variant	Exon 10 of 14	ENST00000378643.8	NP_004620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCG	ENST00000378643.8	c.1157_1163delCCTCCCC	p.Pro386LeufsTer15	frameshift_variant	Exon 10 of 14	1	NM_004629.2	ENSP00000367910.4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000825 AC: 4 AN: 484984 Hom.: 0 AF XY: 0.00000384 AC XY: 1 AN XY: 260356

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

African (AFR) AF: 0.00 AC: 0 AN: 13150

American (AMR) AF: 0.00 AC: 0 AN: 36816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13696

East Asian (EAS) AF: 0.00 AC: 0 AN: 17390

South Asian (SAS) AF: 0.0000148 AC: 1 AN: 67784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3006

European-Non Finnish (NFE) AF: 0.0000107 AC: 3 AN: 280490

Other (OTH) AF: 0.00 AC: 0 AN: 21594

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

Splicing

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

Other links and lift over

dbSNP: rs1554670228; hg19: chr9-35075731;