rs148302546

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

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.11
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]

Genome browser will be placed here

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
EFEMP2NM_016938.5 linkuse as main transcriptc.1212G>A p.Pro404= synonymous_variant 11/11 ENST00000307998.11
EFEMP2NR_037718.2 linkuse as main transcriptn.1337G>A non_coding_transcript_exon_variant 11/12
MUS81NR_146598.2 linkuse as main transcriptn.1813-219C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EFEMP2ENST00000307998.11 linkuse as main transcriptc.1212G>A p.Pro404= synonymous_variant 11/111 NM_016938.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000637
AC:
16
AN:
251240
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000117
AC:
171
AN:
1461856
Hom.:
0
Cov.:
31
AF XY:
0.000111
AC XY:
81
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000137
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000378
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 06, 2023- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 21, 2023- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxSep 23, 2020- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 12, 2020This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.59
CADD
Benign
7.8
DANN
Benign
0.91

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

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

Other links and lift over

dbSNP: rs148302546; hg19: chr11-65634509; COSMIC: COSV57258782; COSMIC: COSV57258782; API