chr6-35452556-C-T

Position:

• chr6-35452556-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021922.3(FANCE):​c.11C>T​(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000851 in 1,174,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: FANCE NM_021922.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.247

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07252383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCE	NM_021922.3	c.11C>T	p.Pro4Leu	missense_variant	1/10	ENST00000229769.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCE	ENST00000229769.3	c.11C>T	p.Pro4Leu	missense_variant	1/10	1	NM_021922.3	P1
FANCE	ENST00000696264.1	c.11C>T	p.Pro4Leu	missense_variant	1/8
FANCE	ENST00000648059.1	c.11C>T	p.Pro4Leu	missense_variant, NMD_transcript_variant	1/11
FANCE	ENST00000696265.1	c.11C>T	p.Pro4Leu	missense_variant, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.51e-7 AC: 1 AN: 1174764 Hom.: 0 Cov.: 30 AF XY: 0.00000175 AC XY: 1 AN XY: 570370

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000104

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2021

The c.11C>T (p.P4L) alteration is located in exon 1 (coding exon 1) of the FANCE gene. This alteration results from a C to T substitution at nucleotide position 11, causing the proline (P) at amino acid position 4 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.039
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.58	T
Polyphen		0.0070	B
Vest4		0.075
MutPred		0.15		Loss of loop (P = 0.0389);
MVP		0.48
MPC		0.11
ClinPred		0.33	T
GERP RS		0.067
Varity_R		0.053
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-35420333;