6-35452490-C-T

Position:

• chr6-35452490-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021922.3(FANCE):​c.-56C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0095 in 1,225,830 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (135 hom.)
• Consequence: FANCE NM_021922.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.749

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-35452490-C-T is Benign according to our data. Variant chr6-35452490-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 356439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCE	NM_021922.3	c.-56C>T		5_prime_UTR_variant	1/10	ENST00000229769.3	NP_068741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCE	ENST00000229769	c.-56C>T		5_prime_UTR_variant	1/10	1	NM_021922.3	ENSP00000229769.2
FANCE	ENST00000648059.1	n.-56C>T		non_coding_transcript_exon_variant	1/11			ENSP00000497902.1
FANCE	ENST00000648059.1	n.-56C>T		5_prime_UTR_variant	1/11			ENSP00000497902.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1785 AN: 152182 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0354

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.0572

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00754

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.00919 AC: 9865 AN: 1073532 Hom.: 135 Cov.: 29 AF XY: 0.00929 AC XY: 4735 AN XY: 509584

Gnomad4 AFR exome AF: 0.00644

Gnomad4 AMR exome AF: 0.0503

Gnomad4 ASJ exome AF: 0.00441

Gnomad4 EAS exome AF: 0.0707

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00386

Gnomad4 NFE exome AF: 0.00704

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0117 AC: 1785 AN: 152298 Hom.: 21 Cov.: 33 AF XY: 0.0131 AC XY: 972 AN XY: 74470

Gnomad4 AFR AF: 0.00604

Gnomad4 AMR AF: 0.0354

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.0572

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.00528

Gnomad4 NFE AF: 0.00754

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00911 Hom.: 2

Bravo AF: 0.0143

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group E Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.9
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4713866; hg19: chr6-35420267; COSMIC: COSV57690840; COSMIC: COSV57690840;