rs633800

Variant names:

• chr11-65871248-G-A
• rs633800
• NM_016938.5:c.276C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-65871248-G-A
• chr11-65871248-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016938.5(EFEMP2):​c.276C>T​(p.His92His) 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:14
• Conservation: PhyloP100: -1.87
• Publications: 29 publications found

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]

EFEMP2 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal recessive, type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, PanelApp Australia, Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive cutis laxa type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal arteriopathy syndrome due to fibulin-4 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thoracic aortic aneurysm

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 163326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.276C>T	p.His92His	synonymous_variant	Exon 4 of 11	ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.401C>T		non_coding_transcript_exon_variant	Exon 4 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.276C>T	p.His92His	synonymous_variant	Exon 4 of 11	1	NM_016938.5	ENSP00000309953.6

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

GnomAD2 exomes AF: 0.447 AC: 112428 AN: 251410 AF XY: 0.468

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 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

African (AFR) AF: 0.151 AC: 5059 AN: 33480

American (AMR) AF: 0.292 AC: 13059 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12925 AN: 26136

East Asian (EAS) AF: 0.198 AC: 7860 AN: 39700

South Asian (SAS) AF: 0.565 AC: 48761 AN: 86258

European-Finnish (FIN) AF: 0.563 AC: 30094 AN: 53410

Middle Eastern (MID) AF: 0.584 AC: 3367 AN: 5768

European-Non Finnish (NFE) AF: 0.510 AC: 566932 AN: 1111976

Other (OTH) AF: 0.470 AC: 28374 AN: 60394

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

African (AFR) AF: 0.161 AC: 6703 AN: 41536

American (AMR) AF: 0.357 AC: 5452 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1723 AN: 3472

East Asian (EAS) AF: 0.203 AC: 1052 AN: 5174

South Asian (SAS) AF: 0.545 AC: 2626 AN: 4820

European-Finnish (FIN) AF: 0.582 AC: 6153 AN: 10568

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35220 AN: 67940

Other (OTH) AF: 0.438 AC: 924 AN: 2110

Alfa AF: 0.450 Hom.: 8418

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Nov 18, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 04, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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