rs193302868

Positions:

• chr11-65867061-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_016938.5(EFEMP2):​c.1189G>A​(p.Ala397Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.76

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• PP5: Variant 11-65867061-C-T is Pathogenic according to our data. Variant chr11-65867061-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39009.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.1189G>A	p.Ala397Thr	missense_variant	11/11	ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.1314G>A		non_coding_transcript_exon_variant	11/12
MUS81	NR_146598.2	n.1813-196C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.1189G>A	p.Ala397Thr	missense_variant	11/11	1	NM_016938.5	ENSP00000309953.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cutis laxa, autosomal recessive, type 1B Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 10, 2024	Variant summary: EFEMP2 c.1189G>A (p.Ala397Thr) results in a non-conservative amino acid change located in the Fibulin, C-terminal Ig-like domain (IPR055088) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251228 control chromosomes (gnomAD). c.1189G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Cutis Laxa (e.g. Sulu_2019). These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 39009). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cutis laxa, autosomal recessive, type 1A Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	.;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	.;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.98	.;D;.
Vest4		0.94
MutPred		0.56		.;Gain of MoRF binding (P = 0.1405);.;
MVP		0.92
MPC		0.93
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.62
gMVP		0.69

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: rs193302868; hg19: chr11-65634532; COSMIC: COSV105149356; COSMIC: COSV105149356;