rs45535043

Positions:

• chr2-55871137-G-A
• chr2-55871137-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039348.3(EFEMP1):​c.1001-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,612,978 control chromosomes in the GnomAD database, including 3,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (269 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2828 hom.)
• Consequence: EFEMP1 NM_001039348.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.26

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-55871137-G-A is Benign according to our data. Variant chr2-55871137-G-A is described in ClinVar as [Benign]. Clinvar id is 257227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EFEMP1	NM_001039348.3	c.1001-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000355426.8	NP_001034437.1
LOC112268416	XR_002959388.2	n.229-2746G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFEMP1	ENST00000355426.8	c.1001-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001039348.3	ENSP00000347596	P1
EFEMP1	ENST00000394555.6	c.1001-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000378058	P1
EFEMP1	ENST00000634374.1	c.360-14C>T		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000489183
EFEMP1	ENST00000635671.1	c.*653-14C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000489578

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8349 AN: 152014 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0272

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0794

GnomAD3 exomes AF: 0.0527 AC: 13203 AN: 250506 Hom.: 432 AF XY: 0.0529 AC XY: 7156 AN XY: 135376

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.0393

Gnomad ASJ exome AF: 0.0791

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0328

Gnomad FIN exome AF: 0.0638

Gnomad NFE exome AF: 0.0680

Gnomad OTH exome AF: 0.0587

GnomAD4 exome AF: 0.0587 AC: 85788 AN: 1460846 Hom.: 2828 Cov.: 33 AF XY: 0.0583 AC XY: 42335 AN XY: 726726

Gnomad4 AFR exome AF: 0.0389

Gnomad4 AMR exome AF: 0.0411

Gnomad4 ASJ exome AF: 0.0761

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0321

Gnomad4 FIN exome AF: 0.0640

Gnomad4 NFE exome AF: 0.0636

Gnomad4 OTH exome AF: 0.0562

GnomAD4 genome AF: 0.0549 AC: 8346 AN: 152132 Hom.: 269 Cov.: 32 AF XY: 0.0552 AC XY: 4102 AN XY: 74378

Gnomad4 AFR AF: 0.0394

Gnomad4 AMR AF: 0.0608

Gnomad4 ASJ AF: 0.0761

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.0274

Gnomad4 FIN AF: 0.0633

Gnomad4 NFE AF: 0.0653

Gnomad4 OTH AF: 0.0786

Alfa AF: 0.0409 Hom.: 36

Bravo AF: 0.0532

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	This variant is associated with the following publications: (PMID: 27884173, 25082885) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Doyne honeycomb retinal dystrophy Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.67

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: rs45535043; hg19: chr2-56098272;