rs143234424

Variant names:

• chr6-35459333-C-T
• rs143234424
• NM_021922.3:c.1116C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_021922.3(FANCE):​c.1116C>T​(p.Ile372Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,802 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: FANCE NM_021922.3 splice_region, synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.14
• Publications: 2 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 6-35459333-C-T is Benign according to our data. Variant chr6-35459333-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 414826.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.

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.1116C>T	p.Ile372Ile	splice_region synonymous	Exon 6 of 10	NP_068741.1
	FANCE	NM_001410876.1		c.1116C>T	p.Ile372Ile	splice_region synonymous	Exon 6 of 8	NP_001397805.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCE	ENST00000229769.3	TSL:1 MANE Select	c.1116C>T	p.Ile372Ile	splice_region synonymous	Exon 6 of 10	ENSP00000229769.2
	FANCE	ENST00000854656.1		c.1119C>T	p.Ile373Ile	splice_region synonymous	Exon 6 of 10	ENSP00000524715.1
	FANCE	ENST00000854658.1		c.1095C>T	p.Ile365Ile	splice_region synonymous	Exon 6 of 10	ENSP00000524717.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 151948 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000378 AC: 95 AN: 251464 AF XY: 0.000383

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.000182 AC XY: 132 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00742 AC: 194 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1112004

Other (OTH) AF: 0.000364 AC: 22 AN: 60394

GnomAD4 genome AF: 0.000263 AC: 40 AN: 151948 Hom.: 1 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74184

African (AFR) AF: 0.00 AC: 0 AN: 41354

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000901 Hom.: 0

Bravo AF: 0.000242

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Fanconi anemia complementation group E (2)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.1
DANN	Benign	0.67
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143234424; hg19: chr6-35427110;