NM_016938.5:c.110C>G

Variant names:

• chr11-65872245-G-C
• rs921412303
• NM_016938.5:c.110C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016938.5(EFEMP2):​c.110C>G​(p.Thr37Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,924 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T37M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EFEMP2 NM_016938.5 missense, splice_region
• Scores: Splicing: ADA: 0.1157
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.41
• Publications: 0 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 2 ACMG points.

• 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.110C>G	p.Thr37Arg	missense splice_region	Exon 2 of 11	NP_058634.4
	EFEMP2	NR_037718.2		n.235C>G		splice_region non_coding_transcript_exon	Exon 2 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.110C>G	p.Thr37Arg	missense splice_region	Exon 2 of 11	ENSP00000309953.6
	EFEMP2	ENST00000531972.5	TSL:1	n.110C>G		splice_region non_coding_transcript_exon	Exon 2 of 12	ENSP00000435295.1
	EFEMP2	ENST00000947418.1		c.110C>G	p.Thr37Arg	missense	Exon 2 of 11	ENSP00000617477.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398924 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689988

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078656

Other (OTH) AF: 0.00 AC: 0 AN: 57986

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.67
Sift	Benign	0.040	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.63
MutPred		0.49		Loss of phosphorylation at T37 (P = 0.0521)
MVP		0.89
MPC		0.54
ClinPred		0.74	D
GERP RS		2.7
PromoterAI		0.16	Neutral
Varity_R		0.20
gMVP		0.92
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.26
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: rs921412303; hg19: chr11-65639716;