11-65869038-A-G

Variant names:

• chr11-65869038-A-G
• rs659824
• NM_016938.5:c.728-409T>C

Variant summary

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

The NM_016938.5(EFEMP2):​c.728-409T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 294,360 control chromosomes in the GnomAD database, including 34,707 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 0.45 (16219 hom., cov: 32)
  • Exomes 𝑓: 0.50 (18488 hom.)
• Consequence: EFEMP2 NM_016938.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

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.728-409T>C		intron	N/A	NP_058634.4
	EFEMP2	NR_037718.2		n.853-409T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.728-409T>C		intron	N/A	ENSP00000309953.6
	EFEMP2	ENST00000527969.1	TSL:1	n.1202-198T>C		intron	N/A
	EFEMP2	ENST00000531972.5	TSL:1	n.728-409T>C		intron	N/A	ENSP00000435295.1

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68471 AN: 151916 Hom.: 16222 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.480

GnomAD4 exome AF: 0.499 AC: 71052 AN: 142326 Hom.: 18488 Cov.: 0 AF XY: 0.508 AC XY: 39150 AN XY: 77134

African (AFR) AF: 0.335 AC: 1432 AN: 4278

American (AMR) AF: 0.330 AC: 1732 AN: 5246

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 1640 AN: 3398

East Asian (EAS) AF: 0.198 AC: 1095 AN: 5532

South Asian (SAS) AF: 0.566 AC: 15280 AN: 26978

European-Finnish (FIN) AF: 0.540 AC: 3465 AN: 6412

Middle Eastern (MID) AF: 0.580 AC: 304 AN: 524

European-Non Finnish (NFE) AF: 0.515 AC: 42674 AN: 82924

Other (OTH) AF: 0.488 AC: 3430 AN: 7034

GnomAD4 genome AF: 0.450 AC: 68490 AN: 152034 Hom.: 16219 Cov.: 32 AF XY: 0.453 AC XY: 33659 AN XY: 74302

African (AFR) AF: 0.343 AC: 14212 AN: 41456

American (AMR) AF: 0.379 AC: 5786 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1721 AN: 3472

East Asian (EAS) AF: 0.210 AC: 1086 AN: 5178

South Asian (SAS) AF: 0.546 AC: 2627 AN: 4814

European-Finnish (FIN) AF: 0.582 AC: 6154 AN: 10568

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35320 AN: 67954

Other (OTH) AF: 0.484 AC: 1021 AN: 2110

Alfa AF: 0.490 Hom.: 8980

Bravo AF: 0.425

Asia WGS AF: 0.391 AC: 1359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.1
DANN	Benign	0.78
PhyloP100		0.078
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: rs659824; hg19: chr11-65636509;