6-35452547-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_021922.3(FANCE):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000428 in 1,168,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: FANCE NM_021922.3 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.157

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 13 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_021922.3 (FANCE) was described as [Likely_pathogenic] in ClinVar as 1696377
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-35452547-T-C is Pathogenic according to our data. Variant chr6-35452547-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1060674.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCE	NM_021922.3	c.2T>C	p.Met1?	start_lost	1/10	ENST00000229769.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCE	ENST00000229769.3	c.2T>C	p.Met1?	start_lost	1/10	1	NM_021922.3	P1
FANCE	ENST00000696264.1	c.2T>C	p.Met1?	start_lost	1/8
FANCE	ENST00000648059.1	c.2T>C	p.Met1?	start_lost, NMD_transcript_variant	1/11
FANCE	ENST00000696265.1	c.2T>C	p.Met1?	start_lost, NMD_transcript_variant	1/9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000428 AC: 5 AN: 1168868 Hom.: 0 Cov.: 30 AF XY: 0.00000882 AC XY: 5 AN XY: 567020

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: 0.00000519

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

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

Jan 04, 2023

Variant summary: FANCE c.2T>C (p.Met1Thr) 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. One of two in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 53280 control chromosomes. Alternatively, N-terminal truncation or extension of the encoded protein can also occur due to translation initiation at an alternative initiation codon. The next downstream in-frame initiation codon is at Met 99. Activation of the potential downstream translation initiation site would result in a shortened protein missing the first 98 amino acids from the protein sequence. Other pathogenic variants have been reported upstream of this alternate codon (e.g. p.Gln31Ter, p.Arg89Ter; ClinVar and HGMD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Fanconi Anemia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Fanconi anemia complementation group E Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change affects the initiator methionine of the FANCE mRNA. The next in-frame methionine is located at codon 99. This variant is present in population databases (no rsID available, gnomAD 0.007%). Disruption of the initiator codon has been observed in individual(s) with clinical features of FANCE-related conditions (PMID: 33084842). ClinVar contains an entry for this variant (Variation ID: 1060674). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.062	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.20
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.79	P
Vest4		0.62
MutPred		0.98		Gain of glycosylation at M1 (P = 8e-04);
MVP		0.78
ClinPred		0.37	T
GERP RS		3.5
Varity_R		0.69
gMVP		0.52

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: rs1462766132; hg19: chr6-35420324;