rs141551053

Positions:

• chr6-35460568-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021922.3(FANCE):​c.1333C>T​(p.Pro445Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,614,092 control chromosomes in the GnomAD database, including 7 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (7 hom.)
• Consequence: FANCE NM_021922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 1.99

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01100862).
• BP6: Variant 6-35460568-C-T is Benign according to our data. Variant chr6-35460568-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134343.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, not_provided=1, Benign=4}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000689 (1007/1461778) while in subpopulation SAS AF= 0.00414 (357/86256). AF 95% confidence interval is 0.00378. There are 7 homozygotes in gnomad4_exome. There are 623 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCE	NM_021922.3	c.1333C>T	p.Pro445Ser	missense_variant	8/10	ENST00000229769.3	NP_068741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCE	ENST00000229769.3	c.1333C>T	p.Pro445Ser	missense_variant	8/10	1	NM_021922.3	ENSP00000229769.2

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00126 AC: 317 AN: 251450 Hom.: 2 AF XY: 0.00148 AC XY: 201 AN XY: 135910

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00402

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000689 AC: 1007 AN: 1461778 Hom.: 7 Cov.: 31 AF XY: 0.000857 AC XY: 623 AN XY: 727194

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00937

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00414

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000250

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74474

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000750 Hom.: 0

Bravo AF: 0.000495

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00114 AC: 139

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group E Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 20, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 04, 2018	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2021	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCE p.Pro445Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs141551053) and ClinVar (classified as benign by Invitae and as a VUS by Illumina). The variant was also identified in control databases in 326 of 282840 chromosomes (2 homozygous) at a frequency of 0.001153 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 106 of 10370 chromosomes (freq: 0.01022), South Asian in 123 of 30616 chromosomes (freq: 0.004018), Other in 12 of 7224 chromosomes (freq: 0.001661), Latino in 19 of 35440 chromosomes (freq: 0.000536), European (non-Finnish) in 55 of 129178 chromosomes (freq: 0.000426), East Asian in 8 of 19954 chromosomes (freq: 0.000401) and African in 3 of 24968 chromosomes (freq: 0.00012), but was not observed in the European (Finnish) population. The p.Pro445 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.75	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.041
Sift	Benign	0.40	T
Sift4G	Uncertain	0.033	D
Polyphen		0.017	B
Vest4		0.11
MVP		0.66
MPC		0.12
ClinPred		0.011	T
GERP RS		1.6
Varity_R		0.044
gMVP		0.079

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs141551053; hg19: chr6-35428345;