NM_016938.5:c.368-11G>A

Variant names:

• chr11-65870669-C-T
• rs181514768
• NM_016938.5:c.368-11G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_016938.5(EFEMP2):​c.368-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,613,912 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (20 hom.)
• Consequence: EFEMP2 NM_016938.5 intron
• Scores: Splicing: ADA: 0.09277
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.251
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal recessive, type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, PanelApp Australia, Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive cutis laxa type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• lethal arteriopathy syndrome due to fibulin-4 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thoracic aortic aneurysm

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 11-65870669-C-T is Benign according to our data. Variant chr11-65870669-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00276 (420/152280) while in subpopulation AMR AF = 0.00484 (74/15290). AF 95% confidence interval is 0.00395. There are 2 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	NM_016938.5	MANE Select	c.368-11G>A		intron	N/A	NP_058634.4
	EFEMP2	NR_037718.2		n.493-11G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.368-11G>A		intron	N/A	ENSP00000309953.6
	EFEMP2	ENST00000527969.1	TSL:1	n.47-11G>A		intron	N/A
	EFEMP2	ENST00000531972.5	TSL:1	n.368-11G>A		intron	N/A	ENSP00000435295.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152162 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00260 AC: 651 AN: 250580 AF XY: 0.00272

Gnomad AFR exome AF: 0.000926

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000420

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00426 AC: 6225 AN: 1461632 Hom.: 20 Cov.: 34 AF XY: 0.00416 AC XY: 3026 AN XY: 727116

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00391 AC: 175 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86256

European-Finnish (FIN) AF: 0.000771 AC: 41 AN: 53202

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00504 AC: 5608 AN: 1111978

Other (OTH) AF: 0.00378 AC: 228 AN: 60394

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152280 Hom.: 2 Cov.: 33 AF XY: 0.00216 AC XY: 161 AN XY: 74468

African (AFR) AF: 0.000843 AC: 35 AN: 41542

American (AMR) AF: 0.00484 AC: 74 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 68012

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00326

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cutis laxa, autosomal recessive, type 1B (3)
-	-	2	not specified (2)
-	-	1	EFEMP2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.093
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.010		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: rs181514768; hg19: chr11-65638140;