11-65868335-T-C

Position:

chr11-65868335-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_016938.5(EFEMP2):c.934A>G(p.Thr312Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000491 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

EFEMP2
NM_016938.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 4.40

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012225091).

BP6

Variant 11-65868335-T-C is Benign according to our data. Variant chr11-65868335-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305379.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP2	NM_016938.5 linkuse as main transcript	c.934A>G	p.Thr312Ala	missense_variant	9/11	ENST00000307998.11
EFEMP2	NR_037718.2 linkuse as main transcript	n.1059A>G		non_coding_transcript_exon_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP2	ENST00000307998.11 linkuse as main transcript	c.934A>G	p.Thr312Ala	missense_variant	9/11	1	NM_016938.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00811

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000613

AC:

154

AN:

251024

Hom.:

AF XY:

0.000530

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00472

Gnomad NFE exome

AF:

0.000397

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000460

AC:

672

AN:

1461538

Hom.:

Cov.:

AF XY:

0.000439

AC XY:

319

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00480

Gnomad4 NFE exome

AF:

0.000362

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000795

AC:

121

AN:

152286

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00811

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000474

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000593

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2020	The EFEMP2 c.934A>G; p.Thr312Ala variant (rs148410446), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.07 % (198 /282,392 alleles) in the Genome Aggregation Database. The threonine at codon 312 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.38). Due to limited information, the clinical significance of the p.Thr312Ala variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	- -
Uncertain significance, 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, 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. -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2020	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 17, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 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

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.25

.;T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.049

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.3

.;.;L

MutationTaster

Benign

0.91

D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.0

N;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.70

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.83, 0.0040

.;P;B

Vest4

0.23, 0.17

MVP

0.86

MPC

0.35

ClinPred

0.056

GERP RS

5.0

Varity_R

0.20

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over