rs3823434

Positions:

• chr6-35458398-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021922.3(FANCE):​c.1071C>T​(p.Leu357=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.03 in 1,614,144 control chromosomes in the GnomAD database, including 1,347 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (102 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1245 hom.)
• Consequence: FANCE NM_021922.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: -0.281

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 6-35458398-C-T is Benign according to our data. Variant chr6-35458398-C-T is described in ClinVar as [Benign]. Clinvar id is 261432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-35458398-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.281 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCE	NM_021922.3	c.1071C>T	p.Leu357=	synonymous_variant	5/10	ENST00000229769.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCE	ENST00000229769.3	c.1071C>T	p.Leu357=	synonymous_variant	5/10	1	NM_021922.3	P1

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4173 AN: 152166 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0294

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0679

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0384

GnomAD3 exomes AF: 0.0402 AC: 10114 AN: 251482 Hom.: 368 AF XY: 0.0407 AC XY: 5526 AN XY: 135916

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.0322

Gnomad ASJ exome AF: 0.0621

Gnomad EAS exome AF: 0.135

Gnomad SAS exome AF: 0.0663

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0238

Gnomad OTH exome AF: 0.0396

GnomAD4 exome AF: 0.0303 AC: 44305 AN: 1461860 Hom.: 1245 Cov.: 32 AF XY: 0.0315 AC XY: 22889 AN XY: 727236

Gnomad4 AFR exome AF: 0.00532

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.0625

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.0636

Gnomad4 FIN exome AF: 0.0376

Gnomad4 NFE exome AF: 0.0223

Gnomad4 OTH exome AF: 0.0370

GnomAD4 genome AF: 0.0274 AC: 4169 AN: 152284 Hom.: 102 Cov.: 32 AF XY: 0.0301 AC XY: 2241 AN XY: 74468

Gnomad4 AFR AF: 0.00638

Gnomad4 AMR AF: 0.0293

Gnomad4 ASJ AF: 0.0671

Gnomad4 EAS AF: 0.136

Gnomad4 SAS AF: 0.0671

Gnomad4 FIN AF: 0.0371

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0389

Alfa AF: 0.0282 Hom.: 188

Bravo AF: 0.0267

Asia WGS AF: 0.113 AC: 390 AN: 3478

EpiCase AF: 0.0267

EpiControl AF: 0.0280

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group E Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 07, 2011	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.7
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3823434; hg19: chr6-35426175; COSMIC: COSV57689203;