rs1307880504
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016938.5(EFEMP2):c.151C>T(p.His51Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000967 in 1,551,488 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000086 ( 0 hom. )
Consequence
EFEMP2
NM_016938.5 missense
NM_016938.5 missense
Scores
12
6
Clinical Significance
Conservation
PhyloP100: 2.62
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EFEMP2 | NM_016938.5 | c.151C>T | p.His51Tyr | missense_variant | 3/11 | ENST00000307998.11 | |
EFEMP2 | NR_037718.2 | n.276C>T | non_coding_transcript_exon_variant | 3/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EFEMP2 | ENST00000307998.11 | c.151C>T | p.His51Tyr | missense_variant | 3/11 | 1 | NM_016938.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000128 AC: 2AN: 156480Hom.: 0 AF XY: 0.0000121 AC XY: 1AN XY: 82330
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GnomAD4 exome AF: 0.00000858 AC: 12AN: 1399368Hom.: 0 Cov.: 31 AF XY: 0.00000580 AC XY: 4AN XY: 690204
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cutis laxa, autosomal recessive, type 1B Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 09, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2021 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a EFEMP2-related disease. This sequence change replaces histidine with tyrosine at codon 51 of the EFEMP2 protein (p.His51Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. - |
EFEMP2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 24, 2023 | The EFEMP2 c.151C>T variant is predicted to result in the amino acid substitution p.His51Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0039% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-65639450-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;T
Sift4G
Benign
T;T;.;T
Polyphen
P;P;.;.
Vest4
MutPred
Loss of disorder (P = 0.0707);Loss of disorder (P = 0.0707);Loss of disorder (P = 0.0707);Loss of disorder (P = 0.0707);
MVP
MPC
0.88
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at