2-55866905-T-C

Position:

• chr2-55866905-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001039348.3(EFEMP1):​c.*168A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00629 in 831,770 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (18 hom.)
• Consequence: EFEMP1 NM_001039348.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.47

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-55866905-T-C is Benign according to our data. Variant chr2-55866905-T-C is described in ClinVar as [Benign]. Clinvar id is 336618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00567 (863/152322) while in subpopulation NFE AF= 0.00897 (610/68026). AF 95% confidence interval is 0.00838. There are 5 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 863 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP1	NM_001039348.3	c.*168A>G		3_prime_UTR_variant	12/12	ENST00000355426.8
LOC112268416	XR_002959388.2	n.229-6978T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP1	ENST00000355426.8	c.*168A>G		3_prime_UTR_variant	12/12	1	NM_001039348.3	P1
EFEMP1	ENST00000394555.6	c.*168A>G		3_prime_UTR_variant	11/11	1		P1
EFEMP1	ENST00000635671.1	c.*1302A>G		3_prime_UTR_variant, NMD_transcript_variant	9/9	2
EFEMP1	ENST00000634374.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00568 AC: 865 AN: 152204 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00897

Gnomad OTH AF: 0.00907

GnomAD4 exome AF: 0.00643 AC: 4369 AN: 679448 Hom.: 18 Cov.: 9 AF XY: 0.00642 AC XY: 2255 AN XY: 351384

Gnomad4 AFR exome AF: 0.000906

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.00216

Gnomad4 NFE exome AF: 0.00762

Gnomad4 OTH exome AF: 0.00697

GnomAD4 genome AF: 0.00567 AC: 863 AN: 152322 Hom.: 5 Cov.: 32 AF XY: 0.00540 AC XY: 402 AN XY: 74484

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00897

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0100 Hom.: 0

Bravo AF: 0.00563

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.91

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: rs1802574; hg19: chr2-56094040;