chr6-35462909-G-A

Variant names:

• chr6-35462909-G-A
• rs9462088
• NM_021922.3:c.1504G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021922.3(FANCE):​c.1504G>A​(p.Ala502Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,614,066 control chromosomes in the GnomAD database, including 8,884 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2963 hom., cov: 32)
  • Exomes 𝑓: 0.068 (5921 hom.)
• Consequence: FANCE NM_021922.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:6 O:1
• Conservation: PhyloP100: 1.05
• Publications: 33 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035373569).
• BP6: Variant 6-35462909-G-A is Benign according to our data. Variant chr6-35462909-G-A is described in ClinVar as Benign. ClinVar VariationId is 134345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

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.1504G>A	p.Ala502Thr	missense	Exon 9 of 10	NP_068741.1	Q9HB96
	FANCE	NM_001410876.1		c.1316+3149G>A		intron	N/A	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.1504G>A	p.Ala502Thr	missense	Exon 9 of 10	ENSP00000229769.2	Q9HB96
	FANCE	ENST00000854656.1		c.1507G>A	p.Ala503Thr	missense	Exon 9 of 10	ENSP00000524715.1
	FANCE	ENST00000854658.1		c.1483G>A	p.Ala495Thr	missense	Exon 9 of 10	ENSP00000524717.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21930 AN: 152152 Hom.: 2952 Cov.: 32

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0738

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.0906 AC: 22784 AN: 251476 AF XY: 0.0894

Gnomad AFR exome AF: 0.369

Gnomad AMR exome AF: 0.0513

Gnomad ASJ exome AF: 0.0669

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0537

Gnomad OTH exome AF: 0.0707

GnomAD4 exome AF: 0.0676 AC: 98786 AN: 1461796 Hom.: 5921 Cov.: 32 AF XY: 0.0693 AC XY: 50420 AN XY: 727192

African (AFR) AF: 0.381 AC: 12745 AN: 33476

American (AMR) AF: 0.0553 AC: 2472 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 1734 AN: 26136

East Asian (EAS) AF: 0.0832 AC: 3305 AN: 39700

South Asian (SAS) AF: 0.161 AC: 13867 AN: 86256

European-Finnish (FIN) AF: 0.0371 AC: 1980 AN: 53416

Middle Eastern (MID) AF: 0.0799 AC: 460 AN: 5756

European-Non Finnish (NFE) AF: 0.0512 AC: 56909 AN: 1111944

Other (OTH) AF: 0.0880 AC: 5314 AN: 60390

GnomAD4 genome AF: 0.144 AC: 21969 AN: 152270 Hom.: 2963 Cov.: 32 AF XY: 0.143 AC XY: 10628 AN XY: 74474

African (AFR) AF: 0.359 AC: 14914 AN: 41510

American (AMR) AF: 0.0736 AC: 1127 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3470

East Asian (EAS) AF: 0.115 AC: 594 AN: 5184

South Asian (SAS) AF: 0.167 AC: 808 AN: 4830

European-Finnish (FIN) AF: 0.0334 AC: 355 AN: 10624

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0530 AC: 3608 AN: 68026

Other (OTH) AF: 0.132 AC: 280 AN: 2114

Alfa AF: 0.0822 Hom.: 4802

Bravo AF: 0.156

TwinsUK AF: 0.0580 AC: 215

ALSPAC AF: 0.0537 AC: 207

ESP6500AA AF: 0.344 AC: 1514

ESP6500EA AF: 0.0523 AC: 450

ExAC AF: 0.0979 AC: 11882

Asia WGS AF: 0.174 AC: 604 AN: 3478

EpiCase AF: 0.0495

EpiControl AF: 0.0535

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	Fanconi anemia complementation group E (5)
-	-	1	not provided (1)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.050
Sift	Benign	0.89	T
Sift4G	Benign	0.53	T
Polyphen		0.0070	B
Vest4		0.043
MPC		0.14
ClinPred		0.0028	T
GERP RS		3.2
Varity_R		0.067
gMVP		0.046
Mutation Taster		=77/23	polymorphism (auto)

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: rs9462088; hg19: chr6-35430686; COSMIC: COSV57690067;