11-65870604-T-C

Variant names:

• chr11-65870604-T-C
• rs148315164
• NM_016938.5:c.422A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_016938.5(EFEMP2):​c.422A>G​(p.His141Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H141L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.790
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a domain EGF-like 2; calcium-binding (size 40) in uniprot entity FBLN4_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_016938.5
• PM2: Very rare variant in population databases, with high coverage

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.422A>G	p.His141Arg	missense	Exon 5 of 11	NP_058634.4
	EFEMP2	NR_037718.2		n.547A>G		non_coding_transcript_exon	Exon 5 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.422A>G	p.His141Arg	missense	Exon 5 of 11	ENSP00000309953.6
	EFEMP2	ENST00000527969.1	TSL:1	n.101A>G		non_coding_transcript_exon	Exon 2 of 4
	EFEMP2	ENST00000531972.5	TSL:1	n.422A>G		non_coding_transcript_exon	Exon 5 of 12	ENSP00000435295.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.18	N
PhyloP100		0.79
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.35
Sift	Benign	0.33	T
Sift4G	Benign	0.35	T
Polyphen		0.97	D
Vest4		0.47
MutPred		0.40		Loss of catalytic residue at L143 (P = 0.1503)
MVP		0.87
MPC		0.74
ClinPred		0.57	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.40
Mutation Taster		=87/13	polymorphism

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: rs148315164; hg19: chr11-65638075;