6-35452545-CATGGCG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_021922.3(FANCE):c.2_7del(p.MetAla1_?2) variant causes a start lost, inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000599 in 1,167,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: FANCE NM_021922.3 start_lost, inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_021922.3 (FANCE) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 1060674
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-35452545-CATGGCG-C is Pathogenic according to our data. Variant chr6-35452545-CATGGCG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1696377.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCE	NM_021922.3	c.2_7del	p.MetAla1_?2	start_lost, inframe_deletion	1/10	ENST00000229769.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCE	ENST00000229769.3	c.2_7del	p.MetAla1_?2	start_lost, inframe_deletion	1/10	1	NM_021922.3	P1
FANCE	ENST00000696264.1	c.2_7del	p.MetAla1_?2	start_lost, inframe_deletion	1/8
FANCE	ENST00000648059.1	c.2_7del	p.MetAla1_?2	start_lost, inframe_deletion, NMD_transcript_variant	1/11
FANCE	ENST00000696265.1	c.2_7del	p.MetAla1_?2	start_lost, inframe_deletion, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000197 AC: 1 AN: 50680 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 30056

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000822

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000599 AC: 7 AN: 1167788 Hom.: 0 AF XY: 0.00000706 AC XY: 4 AN XY: 566242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000169

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 18, 2022

Variant summary: FANCE c.2_7delTGGCGA (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The variant allele was found at a frequency of 2e-05 in 50680 control chromosomes. To our knowledge, no occurrence of c.2_7delTGGCGA in individuals affected with Fanconi Anemia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs755938406; hg19: chr6-35420322;