11-65866636-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016938.5(EFEMP2):c.*282C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 703,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.40

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]

MUS81 (HGNC:29814): (MUS81 structure-specific endonuclease subunit) This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0155778825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP2	NM_016938.5	c.*282C>T		3_prime_UTR_variant	11/11	ENST00000307998.11
EFEMP2	NR_037718.2	n.1607C>T		non_coding_transcript_exon_variant	12/12
MUS81	NR_146598.2	n.1813-621G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP2	ENST00000307998.11	c.*282C>T		3_prime_UTR_variant	11/11	1	NM_016938.5	P1

Frequencies

GnomAD3 genomes AF: 0.000671 AC: 102 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000741 AC: 100 AN: 134870 Hom.: 0 AF XY: 0.000708 AC XY: 52 AN XY: 73440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000490

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000622

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.000482

GnomAD4 exome AF: 0.000820 AC: 452 AN: 551184 Hom.: 0 Cov.: 2 AF XY: 0.000774 AC XY: 231 AN XY: 298362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000691

Gnomad4 ASJ exome AF: 0.0000499

Gnomad4 EAS exome AF: 0.000125

Gnomad4 SAS exome AF: 0.000542

Gnomad4 FIN exome AF: 0.0000297

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.000653

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74392

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000933 Hom.: 0

Bravo AF: 0.000661

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ExAC AF: 0.000261 AC: 6

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B Uncertain: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	0.013
Dann	Uncertain	0.99
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	0.46	N;N
REVEL	Benign	0.083
Sift	Pathogenic	0.0	D;D
Polyphen		0.27	.;B
Vest4		0.095
MutPred		0.35		.;Loss of phosphorylation at T416 (P = 0.0081);
MVP		0.33
ClinPred		0.023	T
GERP RS		-5.8

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

LitVar

Other links and lift over

dbSNP: rs572394429; hg19: chr11-65634107;