Genetic Variant NM_021922.3:c.248+7C>T (chr6-35452800-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_021922.3(FANCE):c.248+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000861 in 1,161,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

FANCE
NM_021922.3 splice_region, intron

Scores

Splicing: ADA: 0.00004310

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.282

Publications

0 publications found

Variant links:

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

FANCE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCE	NM_021922.3 link	c.248+7C>T		splice_region_variant, intron_variant	Intron 1 of 9	ENST00000229769.3	NP_068741.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
FANCE	ENST00000229769.3 link	c.248+7C>T	splice_region_variant, intron_variant	Intron 1 of 9	1	NM_021922.3	ENSP00000229769.2
FANCE	ENST00000696264.1 link	c.248+7C>T	splice_region_variant, intron_variant	Intron 1 of 7			ENSP00000512511.1
FANCE	ENST00000648059.1 link	n.248+7C>T	splice_region_variant, intron_variant	Intron 1 of 10			ENSP00000497902.1
FANCE	ENST00000696265.1 link	n.248+7C>T	splice_region_variant, intron_variant	Intron 1 of 8			ENSP00000512512.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.61e-7

AC:

AN:

1161662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

563062

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24436

American (AMR)

AF:

0.00

AC:

AN:

14924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17724

East Asian (EAS)

AF:

0.00

AC:

AN:

27084

South Asian (SAS)

AF:

0.00

AC:

AN:

44488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3214

European-Non Finnish (NFE)

AF:

0.00000104

AC:

AN:

957176

Other (OTH)

AF:

0.00

AC:

AN:

46616

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

9.7

(source)

DANN

Benign

0.90

PhyloP100

0.28

PromoterAI

-0.017

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000043

dbscSNV1_RF

Benign

0.0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over