rs1346786

Variant names:

• chr2-55881198-C-T
• rs1346786
• NM_001039348.3:c.640+414G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001039348.3(EFEMP1):​c.640+414G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 152,010 control chromosomes in the GnomAD database, including 11,140 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (11140 hom., cov: 32)
• Consequence: EFEMP1 NM_001039348.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.159
• Publications: 30 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• open-angle glaucoma

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• cutis laxa, autosomal recessive, type 1d

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039348.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP1	NM_001039348.3	MANE Select	c.640+414G>A		intron	N/A	NP_001034437.1	Q12805-1
	EFEMP1	NM_001039349.3		c.640+414G>A		intron	N/A	NP_001034438.1	Q12805-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP1	ENST00000355426.8	TSL:1 MANE Select	c.640+414G>A		intron	N/A	ENSP00000347596.3	Q12805-1
	EFEMP1	ENST00000394555.6	TSL:1	c.640+414G>A		intron	N/A	ENSP00000378058.2	Q12805-1
	EFEMP1	ENST00000881458.1		c.790+414G>A		intron	N/A	ENSP00000551517.1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55870 AN: 151892 Hom.: 11125 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.390

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.368 AC: 55931 AN: 152010 Hom.: 11140 Cov.: 32 AF XY: 0.371 AC XY: 27604 AN XY: 74308

African (AFR) AF: 0.439 AC: 18185 AN: 41430

American (AMR) AF: 0.316 AC: 4833 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1241 AN: 3470

East Asian (EAS) AF: 0.834 AC: 4317 AN: 5176

South Asian (SAS) AF: 0.349 AC: 1684 AN: 4826

European-Finnish (FIN) AF: 0.302 AC: 3193 AN: 10572

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21078 AN: 67948

Other (OTH) AF: 0.397 AC: 837 AN: 2110

Alfa AF: 0.333 Hom.: 23199

Bravo AF: 0.373

Asia WGS AF: 0.565 AC: 1963 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.64
PhyloP100		-0.16
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: rs1346786; hg19: chr2-56108333;