6-35466233-C-T

Variant names:

• chr6-35466233-C-T
• rs189384185
• NM_021922.3:c.1510-11C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_021922.3(FANCE):​c.1510-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,579,702 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (10 hom.)
• Consequence: FANCE NM_021922.3 intron
• Scores: Splicing: ADA: 0.0004192
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.274
• Publications: 1 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 6-35466233-C-T is Benign according to our data. Variant chr6-35466233-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210981.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1510-11C>T		intron	N/A	NP_068741.1
	FANCE	NM_001410876.1		c.1317-11C>T		intron	N/A	NP_001397805.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCE	ENST00000229769.3	TSL:1 MANE Select	c.1510-11C>T		intron	N/A	ENSP00000229769.2
	FANCE	ENST00000854656.1		c.1513-11C>T		intron	N/A	ENSP00000524715.1
	FANCE	ENST00000854658.1		c.1489-11C>T		intron	N/A	ENSP00000524717.1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00342

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00278 AC: 698 AN: 251038 AF XY: 0.00267

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00292 AC: 4168 AN: 1427394 Hom.: 10 Cov.: 26 AF XY: 0.00292 AC XY: 2082 AN XY: 712588

African (AFR) AF: 0.000305 AC: 10 AN: 32778

American (AMR) AF: 0.000425 AC: 19 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.000811 AC: 21 AN: 25886

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39564

South Asian (SAS) AF: 0.000608 AC: 52 AN: 85554

European-Finnish (FIN) AF: 0.00998 AC: 533 AN: 53388

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5704

European-Non Finnish (NFE) AF: 0.00315 AC: 3400 AN: 1080584

Other (OTH) AF: 0.00211 AC: 125 AN: 59258

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74458

African (AFR) AF: 0.000481 AC: 20 AN: 41564

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00343 AC: 233 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00188

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Fanconi anemia complementation group E (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.59
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.012
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: rs189384185; hg19: chr6-35434010; COSMIC: COSV104566714;