rs142903218

chr6-35459754-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_021922.3(FANCE):c.1310T>C(p.Met437Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00152 in 1,614,060 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M437V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: FANCE NM_021922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.01

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01204446).
• BP6: Variant 6-35459754-T-C is Benign according to our data. Variant chr6-35459754-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 414821.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCE	NM_021922.3	c.1310T>C	p.Met437Thr	missense_variant	7/10	ENST00000229769.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCE	ENST00000229769.3	c.1310T>C	p.Met437Thr	missense_variant	7/10	1	NM_021922.3	P1

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152208 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0175

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00205 AC: 516 AN: 251464 Hom.: 1 AF XY: 0.00210 AC XY: 285 AN XY: 135908

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00146 AC: 2138 AN: 1461734 Hom.: 4 Cov.: 31 AF XY: 0.00144 AC XY: 1047 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0141

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152326 Hom.: 2 Cov.: 31 AF XY: 0.00259 AC XY: 193 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0175

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00119 Hom.: 3

Bravo AF: 0.000582

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00208 AC: 252

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia complementation group E Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 26, 2021

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Jul 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.018
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Benign	0.049	D
Sift4G	Uncertain	0.017	D
Polyphen		0.47	P
Vest4		0.62
MVP		0.78
MPC		0.41
ClinPred		0.033	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.43

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: rs142903218; hg19: chr6-35427531; COSMIC: COSV104566722;