rs633800

chr11-65871248-G-Achr11-65871248-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016938.5(EFEMP2):c.276C>T(p.His92=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,613,952 control chromosomes in the GnomAD database, including 195,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (14097 hom., cov: 32)
  • Exomes 𝑓: 0.49 (181745 hom.)
• Consequence: EFEMP2 NM_016938.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.87

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-65871248-G-A is Benign according to our data. Variant chr11-65871248-G-A is described in ClinVar as [Benign]. Clinvar id is 163326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-65871248-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP2	NM_016938.5	c.276C>T	p.His92=	synonymous_variant	4/11	ENST00000307998.11
EFEMP2	NR_037718.2	n.401C>T		non_coding_transcript_exon_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP2	ENST00000307998.11	c.276C>T	p.His92=	synonymous_variant	4/11	1	NM_016938.5	P1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60419 AN: 151990 Hom.: 14101 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.434

GnomAD3 exomes AF: 0.447 AC: 112428 AN: 251410 Hom.: 27771 AF XY: 0.468 AC XY: 63596 AN XY: 135906

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.199

Gnomad SAS exome AF: 0.568

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.490 AC: 716431 AN: 1461844 Hom.: 181745 Cov.: 65 AF XY: 0.495 AC XY: 360174 AN XY: 727230

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.292

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.198

Gnomad4 SAS exome AF: 0.565

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.510

Gnomad4 OTH exome AF: 0.470

GnomAD4 genome AF: 0.397 AC: 60413 AN: 152108 Hom.: 14097 Cov.: 32 AF XY: 0.402 AC XY: 29868 AN XY: 74330

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.496

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.545

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.438

Alfa AF: 0.452 Hom.: 8402

Bravo AF: 0.364

Asia WGS AF: 0.376 AC: 1306 AN: 3478

EpiCase AF: 0.526

EpiControl AF: 0.527

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 19, 2014	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	His92His in exon 4 of EFEMP2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 48.2% (4141/8592) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs633800). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Nov 18, 2022

- -

not provided Benign:1

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.276C>T (p.His92His) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 54595/121254 control chromosomes (13690 homozygotes) from ExAC at a frequency of 0.4502532, which is approximately 4027 times the estimated maximal expected allele frequency of a pathogenic EFEMP2 variant (0.0001118), thus it is a common benign polymorphism. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign. Taken together, this variant is classified as benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	2.7
Dann	Benign	0.94

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: rs633800; hg19: chr11-65638719; COSMIC: COSV57259926; COSMIC: COSV57259926;