rs141868759

chr11-65868054-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2 PM5 PP3 BP4_Strong

The NM_016938.5(EFEMP2):c.977G>A(p.Arg326His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00018 in 1,613,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R326G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 6.00

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-65868055-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3065562.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.038262486).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP2	NM_016938.5	c.977G>A	p.Arg326His	missense_variant, splice_region_variant	10/11	ENST00000307998.11
EFEMP2	NR_037718.2	n.1102G>A		splice_region_variant, non_coding_transcript_exon_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP2	ENST00000307998.11	c.977G>A	p.Arg326His	missense_variant, splice_region_variant	10/11	1	NM_016938.5	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000336 AC: 84 AN: 249802 Hom.: 0 AF XY: 0.000311 AC XY: 42 AN XY: 135254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00750

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461266 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 137 AN XY: 726910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00746

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74320

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000555 Hom.: 1

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26582918) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The EFEMP2 p.(Arg326His) variant was not identified in the literature. The variant was found in dbSNP (ID: rs141868759) as "With Uncertain significance allele". ClinVar (the variant is classifed as a VUS, submitted by: Illumina Clinical Services Laboratory, Praxis fuer Humangenetik Tuebingen and Invitae. Associated conditions are Cutis laxa (recessive) and autosomal recessive cutis laxa type 1B.), Clinvitae (variant has been classified as a Variant of Uncertain Significance). Cosmic (FATHMM prediction Pathogenic (score 0.81)) and LOVD 3.0 (variant is listed with unknown effect), databases. The variant was identified in control databases in 86 of 281156 chromosomes at a frequency of 0.000306 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 76 of 10294 chromosomes (freq: 0.007383), Other in 2 of 7172 chromosomes (freq: 0.000279), European (non-Finnish) in 7 of 128034 chromosomes (freq: 0.000055) and Latino in 1 of 35340 chromosomes (freq: 0.000028); it was not observed in the African, East Asian, European (Finnish) and South Asian populations. The p.Arg326 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the R variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.(Arg326His) variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

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

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	Dec 25, 2023	- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2021

The p.R326H variant (also known as c.977G>A), located in coding exon 9 of the EFEMP2 gene, results from a G to A substitution at nucleotide position 977. The arginine at codon 326 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.78, 0.79
MVP		0.98
MPC		1.3
ClinPred		0.26	T
GERP RS		5.4
Varity_R		0.42
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs141868759; hg19: chr11-65635525; COSMIC: COSV57260781; COSMIC: COSV57260781;