dbSNP rs187686630: EFEMP2:c.*115G>A (chr11-65866803-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016938.5(EFEMP2):c.*115G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,376,880 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 15 hom. )

Consequence

EFEMP2
NM_016938.5 3_prime_UTR

Scores

Splicing: ADA: 0.00004855

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.48

Publications

1 publications found

Variant links:

Genes affected

EFEMP2 (HGNC:3219): (EGF containing fibulin extracellular matrix protein 2) A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement and determination of cell fate during development. The protein encoded by this gene contains four EGF2 domains and six calcium-binding EGF2 domains. This gene is necessary for elastic fiber formation and connective tissue development. Defects in this gene are cause of an autosomal recessive cutis laxa syndrome. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jan 2011]

EFEMP2 links:

MUS81 (HGNC:29814): (MUS81 structure-specific endonuclease subunit) This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

MUS81 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 11-65866803-C-T is Benign according to our data. Variant chr11-65866803-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305375.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0021 (319/152134) while in subpopulation NFE AF = 0.0021 (143/68010). AF 95% confidence interval is 0.00182. There are 5 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016938.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EFEMP2	NM_016938.5	MANE Select	c.*115G>A	3_prime_UTR	Exon 11 of 11	NP_058634.4	O95967
EFEMP2	NR_037718.2		n.1530+42G>A	intron	N/A
MUS81	NR_146598.2		n.1813-454C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.*115G>A	3_prime_UTR	Exon 11 of 11	ENSP00000309953.6	O95967
EFEMP2	ENST00000531972.5	TSL:1	n.*73+42G>A	intron	N/A	ENSP00000435295.1	O95967
EFEMP2	ENST00000947418.1		c.*115G>A	3_prime_UTR	Exon 11 of 11	ENSP00000617477.1

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00210

Gnomad OTH

AF:

0.000959

GnomAD2 exomes

AF:

0.00223

AC:

358

AN:

160392

AF XY:

0.00207

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00142

AC:

1744

AN:

1224746

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

841

AN XY:

613030

show subpopulations

African (AFR)

AF:

0.0000354

AC:

AN:

28222

American (AMR)

AF:

0.00

AC:

AN:

36062

Ashkenazi Jewish (ASJ)

AF:

0.0000414

AC:

AN:

24138

East Asian (EAS)

AF:

0.00

AC:

AN:

35148

South Asian (SAS)

AF:

0.0000261

AC:

AN:

76570

European-Finnish (FIN)

AF:

0.0194

AC:

911

AN:

46922

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5350

European-Non Finnish (NFE)

AF:

0.000815

AC:

750

AN:

919720

Other (OTH)

AF:

0.00150

AC:

AN:

52614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

113

226

340

453

566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00210

AC:

319

AN:

152134

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

193

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41496

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0161

AC:

171

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00210

AC:

143

AN:

68010

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00398

Hom.:

Bravo

AF:

0.000480

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cutis laxa, autosomal recessive, type 1B (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000049

dbscSNV1_RF

Benign

0.070

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over