11-61796065-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_004111.6(FEN1):​c.704G>A​(p.Cys235Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

FEN1
NM_004111.6 missense

Scores

12
4
3

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 9.51
Variant links:
Genes affected
FEN1 (HGNC:3650): (flap structure-specific endonuclease 1) The protein encoded by this gene removes 5' overhanging flaps in DNA repair and processes the 5' ends of Okazaki fragments in lagging strand DNA synthesis. Direct physical interaction between this protein and AP endonuclease 1 during long-patch base excision repair provides coordinated loading of the proteins onto the substrate, thus passing the substrate from one enzyme to another. The protein is a member of the XPG/RAD2 endonuclease family and is one of ten proteins essential for cell-free DNA replication. DNA secondary structure can inhibit flap processing at certain trinucleotide repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by the protein encoded by this gene. Therefore, secondary structure can deter the protective function of this protein, leading to site-specific trinucleotide expansions. [provided by RefSeq, Jul 2008]
FADS2 (HGNC:3575): (fatty acid desaturase 2) The protein encoded by this gene is a member of the fatty acid desaturase (FADS) gene family. Desaturase enzymes regulate unsaturation of fatty acids through the introduction of double bonds between defined carbons of the fatty acyl chain. FADS family members are considered fusion products composed of an N-terminal cytochrome b5-like domain and a C-terminal multiple membrane-spanning desaturase portion, both of which are characterized by conserved histidine motifs. This gene is clustered with family members at 11q12-q13.1; this cluster is thought to have arisen evolutionarily from gene duplication based on its similar exon/intron organization. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FEN1NM_004111.6 linkuse as main transcriptc.704G>A p.Cys235Tyr missense_variant 2/2 ENST00000305885.3 NP_004102.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FEN1ENST00000305885.3 linkuse as main transcriptc.704G>A p.Cys235Tyr missense_variant 2/21 NM_004111.6 ENSP00000305480 P1P39748-1
FEN1ENST00000535307.1 linkuse as main transcriptc.128G>A p.Cys43Tyr missense_variant 1/22 ENSP00000460402
FADS2ENST00000574708.5 linkuse as main transcriptn.49+3037G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Non-immune hydrops fetalis Uncertain:1
Uncertain significance, no assertion criteria providedresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterApr 29, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.070
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Benign
-0.45
T
MutationAssessor
Pathogenic
3.6
H
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-9.2
D
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0090
D
Polyphen
1.0
D
Vest4
0.86
MutPred
0.73
Gain of phosphorylation at C235 (P = 0.0371);
MVP
0.84
MPC
1.5
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.98
gMVP
0.85

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-61563537; API