6-35452631-TGCTGCAGGC-TGCTGCAGGCGCTGCAGGC

Variant names:

• chr6-35452631-T-TGCTGCAGGC
• rs780106496
• NM_021922.3:c.97_105dupCTGCAGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_021922.3(FANCE):​c.97_105dupCTGCAGGCG​(p.Leu33_Ala35dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000717 in 1,116,434 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G36G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: FANCE NM_021922.3 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.299
• Publications: 0 publications found

Genes affected

FANCE (HGNC:3586): (FA complementation group E) 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 E. [provided by RefSeq, Jul 2008]

FANCE Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group E

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_021922.3.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021922.3. 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
	FANCE	NM_021922.3	MANE Select	c.97_105dupCTGCAGGCG	p.Leu33_Ala35dup	conservative_inframe_insertion	Exon 1 of 10	NP_068741.1
	FANCE	NM_001410876.1		c.97_105dupCTGCAGGCG	p.Leu33_Ala35dup	conservative_inframe_insertion	Exon 1 of 8	NP_001397805.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCE	ENST00000229769.3	TSL:1 MANE Select	c.97_105dupCTGCAGGCG	p.Leu33_Ala35dup	conservative_inframe_insertion	Exon 1 of 10	ENSP00000229769.2
	FANCE	ENST00000696264.1		c.97_105dupCTGCAGGCG	p.Leu33_Ala35dup	conservative_inframe_insertion	Exon 1 of 8	ENSP00000512511.1
	FANCE	ENST00000648059.1		n.97_105dupCTGCAGGCG		non_coding_transcript_exon	Exon 1 of 11	ENSP00000497902.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000717 AC: 8 AN: 1116434 Hom.: 0 Cov.: 30 AF XY: 0.0000131 AC XY: 7 AN XY: 535348

African (AFR) AF: 0.00 AC: 0 AN: 23120

American (AMR) AF: 0.00 AC: 0 AN: 10004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15450

East Asian (EAS) AF: 0.00 AC: 0 AN: 26600

South Asian (SAS) AF: 0.000105 AC: 3 AN: 28680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3066

European-Non Finnish (NFE) AF: 0.00000425 AC: 4 AN: 941924

Other (OTH) AF: 0.0000223 AC: 1 AN: 44856

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Fanconi anemia complementation group E (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.30
Mutation Taster		=62/38	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs780106496; hg19: chr6-35420408;