NM_001039348.3:c.517+8572A>G

Variant names:

• chr2-55909093-T-C
• rs960993
• NM_001039348.3:c.517+8572A>G

Variant summary

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

The NM_001039348.3(EFEMP1):​c.517+8572A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 152,026 control chromosomes in the GnomAD database, including 8,318 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 0.30 (8318 hom., cov: 32)
• Consequence: EFEMP1 NM_001039348.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.306
• Publications: 5 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP1	NM_001039348.3	c.517+8572A>G		intron_variant	Intron 5 of 11	ENST00000355426.8	NP_001034437.1
EFEMP1	NM_001039349.3	c.517+8572A>G		intron_variant	Intron 4 of 10		NP_001034438.1
EFEMP1	XM_005264205.5	c.517+8572A>G		intron_variant	Intron 5 of 9		XP_005264262.2
EFEMP1	XM_017003586.3	c.517+8572A>G		intron_variant	Intron 4 of 8		XP_016859075.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP1	ENST00000355426.8	c.517+8572A>G		intron_variant	Intron 5 of 11	1	NM_001039348.3	ENSP00000347596.3
EFEMP1	ENST00000394555.6	c.517+8572A>G		intron_variant	Intron 4 of 10	1		ENSP00000378058.2
EFEMP1	ENST00000634374.1	c.115+8572A>G		intron_variant	Intron 1 of 5	5		ENSP00000489183.1
EFEMP1	ENST00000635671.1	n.*409+8572A>G		intron_variant	Intron 4 of 8	2		ENSP00000489578.1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45177 AN: 151908 Hom.: 8306 Cov.: 32

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.0314

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.299

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

GnomAD4 genome AF: 0.297 AC: 45224 AN: 152026 Hom.: 8318 Cov.: 32 AF XY: 0.294 AC XY: 21821 AN XY: 74318

African (AFR) AF: 0.516 AC: 21375 AN: 41448

American (AMR) AF: 0.243 AC: 3701 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1014 AN: 3470

East Asian (EAS) AF: 0.0313 AC: 162 AN: 5182

South Asian (SAS) AF: 0.302 AC: 1449 AN: 4804

European-Finnish (FIN) AF: 0.179 AC: 1897 AN: 10602

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14724 AN: 67944

Other (OTH) AF: 0.298 AC: 631 AN: 2114

Alfa AF: 0.255 Hom.: 731

Bravo AF: 0.307

Asia WGS AF: 0.200 AC: 694 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.37
PhyloP100		-0.31
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: rs960993; hg19: chr2-56136228;