rs2234473

chr11-65867062-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_016938.5(EFEMP2):c.1188C>T(p.Ser396=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,614,094 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: EFEMP2 NM_016938.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.00400

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-65867062-G-A is Benign according to our data. Variant chr11-65867062-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305377.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=4, Uncertain_significance=1}. Variant chr11-65867062-G-A is described in Lovd as [Benign]. Variant chr11-65867062-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.004 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00246 (3593/1461820) while in subpopulation NFE AF= 0.00266 (2959/1111998). AF 95% confidence interval is 0.00258. There are 6 homozygotes in gnomad4_exome. There are 1746 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP2	NM_016938.5	c.1188C>T	p.Ser396=	synonymous_variant	11/11	ENST00000307998.11
EFEMP2	NR_037718.2	n.1313C>T		non_coding_transcript_exon_variant	11/12
MUS81	NR_146598.2	n.1813-195G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP2	ENST00000307998.11	c.1188C>T	p.Ser396=	synonymous_variant	11/11	1	NM_016938.5	P1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152156 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00215 AC: 539 AN: 251228 Hom.: 1 AF XY: 0.00206 AC XY: 280 AN XY: 135866

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0116

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00246 AC: 3593 AN: 1461820 Hom.: 6 Cov.: 31 AF XY: 0.00240 AC XY: 1746 AN XY: 727208

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00974

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00167 AC: 255 AN: 152274 Hom.: 2 Cov.: 33 AF XY: 0.00205 AC XY: 153 AN XY: 74454

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00202 Hom.: 0

Bravo AF: 0.00109

EpiCase AF: 0.00196

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 12, 2015	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2017	Variant summary: The EFEMP2 c.1188C>T (p.Ser396Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a damaging outcome for this variant. 3/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts that this variant may create a new binding site for SC35. However, these predictions have yet to be confirmed by functional studies. This variant was found in 240/120628 control chromosomes from ExAC, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.011343 (74/6524). This frequency is about 101 times the estimated maximal expected allele frequency of a pathogenic EFEMP2 variant (0.0001118), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. Similar frequency in European (Finnish) subpopulation (0.01098; 283/25780 chromosomes) has also been detected in gnomAD database, including 2 homozygotes. One clinical diagnostic laboratory (via ClinVar) has classified this variant as uncertain significance without evidence to independently evaluate. To our knowledge, this variant has not been published in affected individuals in literature. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	EFEMP2: BP4, BP7 -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Mar 31, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2019

This alteration is classified as 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. -

EFEMP2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	11
Dann	Benign	0.89

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

LitVar

Other links and lift over

dbSNP: rs2234473; hg19: chr11-65634533; COSMIC: COSV57261728; COSMIC: COSV57261728;