rs45535043

Variant names:

• chr2-55871137-G-A
• rs45535043
• NM_001039348.3:c.1001-14C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039348.3(EFEMP1):​c.1001-14C>T variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.26
• Publications: 7 publications found

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]

EFEMP1 Gene-Disease associations (from GenCC):

• Doyne honeycomb retinal dystrophy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet, G2P
• cutis laxa, autosomal recessive, type 1d

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• cutis laxa

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC112268416 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
EFEMP1	NM_001039348.3	c.1001-14C>T		intron_variant	Intron 9 of 11	ENST00000355426.8	NP_001034437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP1	ENST00000355426.8	c.1001-14C>T		intron_variant	Intron 9 of 11	1	NM_001039348.3	ENSP00000347596.3
EFEMP1	ENST00000394555.6	c.1001-14C>T		intron_variant	Intron 8 of 10	1		ENSP00000378058.2
EFEMP1	ENST00000634374.1	c.359-14C>T		intron_variant	Intron 3 of 5	5		ENSP00000489183.1
EFEMP1	ENST00000635671.1	n.*653-14C>T		intron_variant	Intron 6 of 8	2		ENSP00000489578.1

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

GnomAD2 exomes AF: 0.0527 AC: 13203 AN: 250506 AF XY: 0.0529

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 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

African (AFR) AF: 0.0389 AC: 1301 AN: 33438

American (AMR) AF: 0.0411 AC: 1832 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 1985 AN: 26100

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39688

South Asian (SAS) AF: 0.0321 AC: 2764 AN: 86238

European-Finnish (FIN) AF: 0.0640 AC: 3411 AN: 53332

Middle Eastern (MID) AF: 0.0816 AC: 470 AN: 5762

European-Non Finnish (NFE) AF: 0.0636 AC: 70627 AN: 1111332

Other (OTH) AF: 0.0562 AC: 3388 AN: 60330

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

African (AFR) AF: 0.0394 AC: 1636 AN: 41510

American (AMR) AF: 0.0608 AC: 928 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 264 AN: 3470

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5158

South Asian (SAS) AF: 0.0274 AC: 132 AN: 4820

European-Finnish (FIN) AF: 0.0633 AC: 671 AN: 10592

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0653 AC: 4437 AN: 67992

Other (OTH) AF: 0.0786 AC: 166 AN: 2112

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 25082885) -

not specified Benign:2

Dec 15, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Doyne honeycomb retinal dystrophy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45535043; hg19: chr2-56098272;