chr11-65866939-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_016938.5(EFEMP2):ā€‹c.1311T>Gā€‹(p.Phe437Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

EFEMP2
NM_016938.5 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.522
Variant links:
Genes affected
EFEMP2 (HGNC:3219): (EGF containing fibulin extracellular matrix protein 2) A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement and determination of cell fate during development. The protein encoded by this gene contains four EGF2 domains and six calcium-binding EGF2 domains. This gene is necessary for elastic fiber formation and connective tissue development. Defects in this gene are cause of an autosomal recessive cutis laxa syndrome. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]
MUS81 (HGNC:29814): (MUS81 structure-specific endonuclease subunit) This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EFEMP2NM_016938.5 linkuse as main transcriptc.1311T>G p.Phe437Leu missense_variant 11/11 ENST00000307998.11
EFEMP2NR_037718.2 linkuse as main transcriptn.1436T>G non_coding_transcript_exon_variant 11/12
MUS81NR_146598.2 linkuse as main transcriptn.1813-318A>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EFEMP2ENST00000307998.11 linkuse as main transcriptc.1311T>G p.Phe437Leu missense_variant 11/111 NM_016938.5 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461876
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021EFEMP2 NM_016938.4 exon 11 p.Phe437Leu (c.1311T>G): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Benign
-0.15
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D
Eigen
Benign
-0.49
Eigen_PC
Benign
-0.39
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.34
T
MetaSVM
Benign
-0.64
T
MutationAssessor
Uncertain
2.0
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-2.1
N
REVEL
Uncertain
0.44
Sift
Benign
0.043
D
Sift4G
Benign
0.084
T
Polyphen
0.13
B
Vest4
0.29
MutPred
0.53
Gain of MoRF binding (P = 0.096);
MVP
0.75
MPC
0.44
ClinPred
0.43
T
GERP RS
-0.12
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.13
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.63
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.63
Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1591064625; hg19: chr11-65634410; API