rs148410446

Variant summary

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

The NM_016938.5(EFEMP2):ā€‹c.934A>Gā€‹(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: š‘“ 0.00079 ( 0 hom., cov: 33)
Exomes š‘“: 0.00046 ( 0 hom. )

Consequence

EFEMP2
NM_016938.5 missense

Scores

2
17

Clinical Significance

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

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: {Likely_benign=3, Uncertain_significance=4, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EFEMP2NM_016938.5 linkuse as main transcriptc.934A>G p.Thr312Ala missense_variant 9/11 ENST00000307998.11
EFEMP2NR_037718.2 linkuse as main transcriptn.1059A>G non_coding_transcript_exon_variant 9/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EFEMP2ENST00000307998.11 linkuse as main transcriptc.934A>G p.Thr312Ala missense_variant 9/111 NM_016938.5 P1

Frequencies

GnomAD3 genomes
AF:
0.000795
AC:
121
AN:
152168
Hom.:
0
Cov.:
33
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.:
0
AF XY:
0.000530
AC XY:
72
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.:
0
Cov.:
32
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.:
0
Cov.:
33
AF XY:
0.00107
AC XY:
80
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.:
0
Bravo
AF:
0.000193
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000593
AC:
72
EpiCase
AF:
0.000382
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign: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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 28, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 25, 2020The 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. -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsFeb 03, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 07, 2020- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 26, 2024Variant summary: EFEMP2 c.934A>G (p.Thr312Ala) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251024 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EFEMP2 causing Autosomal Recessive Cutis Laxa (0.00061 vs 0.00071), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.934A>G in individuals affected with Autosomal Recessive Cutis Laxa and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 305379). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJan 17, 2023- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 09, 2019This 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
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
21
DANN
Benign
0.72
DEOGEN2
Benign
0.25
.;T;T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.74
T;T;T
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.012
T;T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.3
.;.;L
MutationTaster
Benign
0.91
D;D
PrimateAI
Benign
0.47
T
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
T
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.

Other links and lift over

dbSNP: rs148410446; hg19: chr11-65635806; API