Genetic Variant FANCE:p.Arg371Gly (chr6-35458438-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_021922.3(FANCE):c.1111C>G(p.Arg371Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R371W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

FANCE
NM_021922.3 missense, splice_region

Scores

Splicing: ADA: 0.04956

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.41

Publications

0 publications found

Variant links:

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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-35458438-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 566449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

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.1111C>G	p.Arg371Gly	missense splice_region	Exon 5 of 10	NP_068741.1	Q9HB96
	FANCE	NM_001410876.1		c.1111C>G	p.Arg371Gly	missense splice_region	Exon 5 of 8	NP_001397805.1	A0A8Q3WL50

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCE	ENST00000229769.3	TSL:1 MANE Select	c.1111C>G	p.Arg371Gly	missense splice_region	Exon 5 of 10	ENSP00000229769.2	Q9HB96
FANCE	ENST00000854656.1		c.1114C>G	p.Arg372Gly	missense splice_region	Exon 5 of 10	ENSP00000524715.1
FANCE	ENST00000854658.1		c.1090C>G	p.Arg364Gly	missense splice_region	Exon 5 of 10	ENSP00000524717.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.79

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.6

PhyloP100

1.4

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-4.7

REVEL

Benign

0.25

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.72

MutPred

0.65

Loss of helix (P = 0.028)

MVP

0.65

MPC

0.60

ClinPred

0.99

GERP RS

3.5

Varity_R

0.73

gMVP

0.47

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.050

dbscSNV1_RF

Benign

0.32

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over