rs148302546
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Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_016938.5(EFEMP2):c.1212G>A(p.Pro404=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,614,050 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
EFEMP2
NM_016938.5 synonymous
NM_016938.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.11
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 Benign. Variant got -11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
BP6
Variant 11-65867038-C-T is Benign according to our data. Variant chr11-65867038-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 472811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-3.11 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EFEMP2 | NM_016938.5 | c.1212G>A | p.Pro404= | synonymous_variant | 11/11 | ENST00000307998.11 | |
EFEMP2 | NR_037718.2 | n.1337G>A | non_coding_transcript_exon_variant | 11/12 | |||
MUS81 | NR_146598.2 | n.1813-219C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EFEMP2 | ENST00000307998.11 | c.1212G>A | p.Pro404= | synonymous_variant | 11/11 | 1 | NM_016938.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152194Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251240Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135884
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GnomAD4 exome AF: 0.000117 AC: 171AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 81AN XY: 727228
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74354
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ClinVar
Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cutis laxa, autosomal recessive, type 1B Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 21, 2023 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 12, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at