2-55866825-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001039348.3(EFEMP1):c.*248A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 462,944 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (30 hom.)
• Consequence: EFEMP1 NM_001039348.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.754

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-55866825-T-G is Benign according to our data. Variant chr2-55866825-T-G is described in ClinVar as [Benign]. Clinvar id is 336616.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFEMP1	NM_001039348.3	c.*248A>C		3_prime_UTR_variant	12/12	ENST00000355426.8
LOC112268416	XR_002959388.2	n.229-7058T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFEMP1	ENST00000355426.8	c.*248A>C		3_prime_UTR_variant	12/12	1	NM_001039348.3	P1
EFEMP1	ENST00000394555.6	c.*248A>C		3_prime_UTR_variant	11/11	1		P1
EFEMP1	ENST00000635671.1	c.*1382A>C		3_prime_UTR_variant, NMD_transcript_variant	9/9	2

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 462 AN: 152186 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00382

GnomAD4 exome AF: 0.00327 AC: 1016 AN: 310640 Hom.: 30 Cov.: 4 AF XY: 0.00324 AC XY: 536 AN XY: 165536

Gnomad4 AFR exome AF: 0.000972

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0448

Gnomad4 SAS exome AF: 0.00196

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000374

Gnomad4 OTH exome AF: 0.00529

GnomAD4 genome AF: 0.00304 AC: 463 AN: 152304 Hom.: 16 Cov.: 32 AF XY: 0.00342 AC XY: 255 AN XY: 74470

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0684

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.00343

Asia WGS AF: 0.0410 AC: 141 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Doyne honeycomb retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.61
Cadd	Benign	6.6
Dann	Benign	0.73

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: rs117386259; hg19: chr2-56093960;