11-65871234-G-T

Variant names:

• chr11-65871234-G-T
• NM_016938.5:c.290C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016938.5(EFEMP2):​c.290C>A​(p.Pro97Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P97L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2629062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.290C>A	p.Pro97Gln	missense_variant	Exon 4 of 11	ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.415C>A		non_coding_transcript_exon_variant	Exon 4 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.290C>A	p.Pro97Gln	missense_variant	Exon 4 of 11	1	NM_016938.5	ENSP00000309953.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P97Q variant (also known as c.290C>A), located in coding exon 3 of the EFEMP2 gene, results from a C to A substitution at nucleotide position 290. The proline at codon 97 is replaced by glutamine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	0.072
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.019	T;T;.;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.8	.;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.49	N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.25	T;T;.;T
Polyphen		0.94	P;B;.;.
Vest4		0.33
MutPred		0.32		Loss of glycosylation at P97 (P = 0.0112);Loss of glycosylation at P97 (P = 0.0112);Loss of glycosylation at P97 (P = 0.0112);Loss of glycosylation at P97 (P = 0.0112);
MVP		0.78
MPC		0.33
ClinPred		0.48	T
GERP RS		4.8
Varity_R		0.094
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-65638705;