2-55867075-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_001039348.3(EFEMP1):c.1480T>C(p.Ter494GlnextTer29) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFEMP1 NM_001039348.3 stop_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.61

Genes affected

EFEMP1 (HGNC:3218): (EGF containing fibulin extracellular matrix protein 1) This gene encodes a member of the fibulin family of extracellular matrix glycoproteins. Like all members of this family, the encoded protein contains tandemly repeated epidermal growth factor-like repeats followed by a C-terminus fibulin-type domain. This gene is upregulated in malignant gliomas and may play a role in the aggressive nature of these tumors. Mutations in this gene are associated with Doyne honeycomb retinal dystrophy. Alternatively spliced transcript variants that encode the same protein have been described.[provided by RefSeq, Nov 2009]

LOC112268416 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-55867075-A-G is Pathogenic according to our data. Variant chr2-55867075-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1294422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.0337291).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP1	NM_001039348.3	c.1480T>C	p.Ter494GlnextTer29	stop_lost	12/12	ENST00000355426.8
LOC112268416	XR_002959388.2	n.229-6808A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP1	ENST00000355426.8	c.1480T>C	p.Ter494GlnextTer29	stop_lost	12/12	1	NM_001039348.3	P1
EFEMP1	ENST00000394555.6	c.1480T>C	p.Ter494GlnextTer29	stop_lost	11/11	1		P1
EFEMP1	ENST00000634374.1	c.841T>C	p.Ter281GlnextTer29	stop_lost	6/6	5
EFEMP1	ENST00000635671.1	c.*1132T>C		3_prime_UTR_variant, NMD_transcript_variant	9/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Glaucoma 1, open angle, H Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 18, 2024

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 21, 2023

This sequence change disrupts the translational stop signal of the EFEMP1 mRNA. It is expected to extend the length of the EFEMP1 protein by 29 additional amino acid residues. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this protein extension affects EFEMP1 function (PMID: 34923728). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1294422). This protein extension has been observed in individual(s) with juvenile‚Äê onset primary open‚Äêangle glaucoma (PMID: 34923728). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Glaucoma of childhood Pathogenic:1

Pathogenic, no assertion criteria provided

research

Janey Wiggs Laboratory, Massachusetts Eye and Ear, Harvard Medical School

Sep 23, 2021

The c.1480T>C variant in EFEMP1 causes the stop codon to be lost and adds an additional 29 amino acids to the C-terminus of the protein. This variant has been reported in a Filipino family (Collantes et al, in revision) and segregated with disease in 24 individuals (17 affected) and was absent from last population studies. Additionally, invitro functional studies indicate that c.1480T>C causes intracellular protein aggregation potentially related to disease pathogenesis. In summary the c.1480T>C variant meets criteria to be classified as pathogenic based upon segregation studies, absence from controls and functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	17
Dann	Benign	0.90
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	N;N;N;N
Vest4		0.074
GERP RS		5.3

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: chr2-56094210;