6-35452546-A-G

Variant names:

• chr6-35452546-A-G
• rs1767144343
• NM_021922.3:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_021922.3(FANCE):​c.1A>G​(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 0.000000856 in 1,168,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: FANCE NM_021922.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.395
• Publications: 0 publications found

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]

FANCE Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group E

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 15 pathogenic variants. Next in-frame start position is after 99 codons. Genomic position: 35455793. Lost 0.183 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021922.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCE	NM_021922.3	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	NP_068741.1	Q9HB96
	FANCE	NM_001410876.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 8	NP_001397805.1	A0A8Q3WL50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCE	ENST00000229769.3	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENSP00000229769.2	Q9HB96
	FANCE	ENST00000854656.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENSP00000524715.1
	FANCE	ENST00000854658.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 10	ENSP00000524717.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.56e-7 AC: 1 AN: 1168208 Hom.: 0 Cov.: 30 AF XY: 0.00000176 AC XY: 1 AN XY: 566628

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24664

American (AMR) AF: 0.00 AC: 0 AN: 18330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18626

East Asian (EAS) AF: 0.00 AC: 0 AN: 26938

South Asian (SAS) AF: 0.0000241 AC: 1 AN: 41528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3462

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 962908

Other (OTH) AF: 0.00 AC: 0 AN: 46986

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.030	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.0	T
PhyloP100		0.40
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.21
Sift	Benign	0.044	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.28	B
Vest4		0.63
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.169)
MVP		0.62
ClinPred		0.43	T
GERP RS		3.0
PromoterAI		-0.19	Neutral
Varity_R		0.57
gMVP		0.49
Mutation Taster		=19/181	disease causing

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

Other links and lift over

dbSNP: rs1767144343; hg19: chr6-35420323;