11-65868088-G-A

Variant names:

• chr11-65868088-G-A
• rs594689
• NM_016938.5:c.975-32C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016938.5(EFEMP2):​c.975-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,608,318 control chromosomes in the GnomAD database, including 195,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (14043 hom., cov: 31)
  • Exomes 𝑓: 0.49 (181043 hom.)
• Consequence: EFEMP2 NM_016938.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.57
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-65868088-G-A is Benign according to our data. Variant chr11-65868088-G-A is described in ClinVar as Benign. ClinVar VariationId is 1255373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFEMP2	NM_016938.5	c.975-32C>T		intron_variant	Intron 9 of 10	ENST00000307998.11	NP_058634.4
EFEMP2	NR_037718.2	n.1100-32C>T		intron_variant	Intron 9 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFEMP2	ENST00000307998.11	c.975-32C>T		intron_variant	Intron 9 of 10	1	NM_016938.5	ENSP00000309953.6

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60183 AN: 151854 Hom.: 14046 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.434

GnomAD2 exomes AF: 0.448 AC: 108905 AN: 243216 AF XY: 0.468

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.489

Gnomad EAS exome AF: 0.204

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.518

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.490 AC: 714066 AN: 1456346 Hom.: 181043 Cov.: 34 AF XY: 0.496 AC XY: 358827 AN XY: 724120

African (AFR) AF: 0.148 AC: 4929 AN: 33346

American (AMR) AF: 0.293 AC: 12951 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12879 AN: 26044

East Asian (EAS) AF: 0.200 AC: 7923 AN: 39578

South Asian (SAS) AF: 0.566 AC: 48645 AN: 86020

European-Finnish (FIN) AF: 0.564 AC: 29699 AN: 52692

Middle Eastern (MID) AF: 0.579 AC: 2944 AN: 5088

European-Non Finnish (NFE) AF: 0.510 AC: 565798 AN: 1109226

Other (OTH) AF: 0.471 AC: 28298 AN: 60110

GnomAD4 genome AF: 0.396 AC: 60180 AN: 151972 Hom.: 14043 Cov.: 31 AF XY: 0.401 AC XY: 29767 AN XY: 74278

African (AFR) AF: 0.157 AC: 6518 AN: 41486

American (AMR) AF: 0.357 AC: 5446 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1716 AN: 3468

East Asian (EAS) AF: 0.209 AC: 1074 AN: 5148

South Asian (SAS) AF: 0.545 AC: 2628 AN: 4826

European-Finnish (FIN) AF: 0.582 AC: 6154 AN: 10574

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35162 AN: 67906

Other (OTH) AF: 0.438 AC: 922 AN: 2104

Alfa AF: 0.468 Hom.: 7966

Bravo AF: 0.363

Asia WGS AF: 0.379 AC: 1320 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cutis laxa, autosomal recessive, type 1B Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.9
DANN	Benign	0.82
PhyloP100		2.6
PromoterAI		-0.0083	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs594689; hg19: chr11-65635559;