chr6-35452576-G-A

Variant names:

• chr6-35452576-G-A
• rs753304968
• NM_021922.3:c.31G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021922.3(FANCE):​c.31G>A​(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,333,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: FANCE NM_021922.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.344
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028799146).

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.31G>A	p.Ala11Thr	missense	Exon 1 of 10	NP_068741.1	Q9HB96
	FANCE	NM_001410876.1		c.31G>A	p.Ala11Thr	missense	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.31G>A	p.Ala11Thr	missense	Exon 1 of 10	ENSP00000229769.2	Q9HB96
	FANCE	ENST00000854656.1		c.31G>A	p.Ala11Thr	missense	Exon 1 of 10	ENSP00000524715.1
	FANCE	ENST00000854658.1		c.31G>A	p.Ala11Thr	missense	Exon 1 of 10	ENSP00000524717.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 151962 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 8 AN: 58348 AF XY: 0.0000580

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.000186

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000266

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000446 AC: 527 AN: 1181254 Hom.: 0 Cov.: 30 AF XY: 0.000394 AC XY: 226 AN XY: 574032

African (AFR) AF: 0.0000803 AC: 2 AN: 24900

American (AMR) AF: 0.000507 AC: 10 AN: 19730

Ashkenazi Jewish (ASJ) AF: 0.0000513 AC: 1 AN: 19492

East Asian (EAS) AF: 0.0000370 AC: 1 AN: 26992

South Asian (SAS) AF: 0.0000229 AC: 1 AN: 43748

European-Finnish (FIN) AF: 0.000276 AC: 7 AN: 25372

Middle Eastern (MID) AF: 0.000876 AC: 3 AN: 3424

European-Non Finnish (NFE) AF: 0.000504 AC: 489 AN: 969998

Other (OTH) AF: 0.000273 AC: 13 AN: 47598

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152074 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74356

African (AFR) AF: 0.0000723 AC: 3 AN: 41516

American (AMR) AF: 0.000327 AC: 5 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000383 AC: 26 AN: 67916

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000486 Hom.: 0

Bravo AF: 0.000193

ExAC AF: 0.0000774 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Fanconi anemia complementation group E (3)
-	1	-	FANCE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.34
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.028
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.016	D
Polyphen		0.0010	B
Vest4		0.075
MutPred		0.080		Gain of glycosylation at A11 (P = 0.0162)
MVP		0.39
MPC		0.10
ClinPred		0.052	T
GERP RS		-3.7
PromoterAI		0.086	Neutral
Varity_R		0.055
gMVP		0.20
Mutation Taster		=99/1	polymorphism

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: rs753304968; hg19: chr6-35420353;