rs769779495

Positions:

• chr6-35452791-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_021922.3(FANCE):​c.246G>A​(p.Glu82=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,315,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: FANCE NM_021922.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001389
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.246

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 Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-35452791-G-A is Benign according to our data. Variant chr6-35452791-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 414820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.246 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCE	NM_021922.3	c.246G>A	p.Glu82=	splice_region_variant, synonymous_variant	1/10	ENST00000229769.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCE	ENST00000229769.3	c.246G>A	p.Glu82=	splice_region_variant, synonymous_variant	1/10	1	NM_021922.3	P1
FANCE	ENST00000696264.1	c.246G>A	p.Glu82=	splice_region_variant, synonymous_variant	1/8
FANCE	ENST00000648059.1	c.246G>A	p.Glu82=	splice_region_variant, synonymous_variant, NMD_transcript_variant	1/11
FANCE	ENST00000696265.1	c.246G>A	p.Glu82=	splice_region_variant, synonymous_variant, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000278 AC: 1 AN: 35924 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 21676

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: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000327 AC: 38 AN: 1162994 Hom.: 0 Cov.: 30 AF XY: 0.0000301 AC XY: 17 AN XY: 563934

Gnomad4 AFR exome AF: 0.000492

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000368

Gnomad4 SAS exome AF: 0.0000446

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000188

Gnomad4 OTH exome AF: 0.0000856

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74374

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000223

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group E Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

FANCE-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs769779495; hg19: chr6-35420568;