rs111550973

Positions:

• chr11-65870662-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016938.5(EFEMP2):​c.368-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,613,956 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: EFEMP2 NM_016938.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002104
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.98

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 11-65870662-C-T is Benign according to our data. Variant chr11-65870662-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-65870662-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00209 (318/152266) while in subpopulation NFE AF= 0.00393 (267/68012). AF 95% confidence interval is 0.00354. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.368-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.493-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.368-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_016938.5	ENSP00000309953	P1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00168 AC: 422 AN: 250690 Hom.: 1 AF XY: 0.00167 AC XY: 226 AN XY: 135596

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00323 AC: 4728 AN: 1461690 Hom.: 12 Cov.: 34 AF XY: 0.00312 AC XY: 2270 AN XY: 727160

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000638

Gnomad4 NFE exome AF: 0.00410

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00192 AC XY: 143 AN XY: 74458

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00393

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00264 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Feb 04, 2014	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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.368-4G>A variant involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 219/121494 control chromosomes (1 homozygote) including ExAC at a frequency of 0.0018026, which is approximately 16 times the estimated maximal expected allele frequency of a pathogenic EFEMP2 variant (0.0001118), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories (via ClinVar) have classified this variant as benign. To our knowledge, the variant of interest has not been reported 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	Apr 01, 2024	EFEMP2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2021	This variant is associated with the following publications: (PMID: 26017485) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

368-4G>A in intron 4 of EFEMP2: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 0.3% (30/8592) of European American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS; dbSNP rs111550973). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.36
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.050		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: rs111550973; hg19: chr11-65638133;