NM_016938.5:c.775A>G

Variant names:

• chr11-65868582-T-C
• rs601314
• NM_016938.5:c.775A>G

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.775A>G​(p.Ile259Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 1,613,852 control chromosomes in the GnomAD database, including 781,211 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I259A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.91 (63941 hom., cov: 32)
  • Exomes 𝑓: 0.99 (717270 hom.)
• Consequence: EFEMP2 NM_016938.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 0.137
• Publications: 42 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: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• 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 (MetaRNN=4.314085E-6).
• BP6: Variant 11-65868582-T-C is Benign according to our data. Variant chr11-65868582-T-C is described in ClinVar as Benign. ClinVar VariationId is 39015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	NM_016938.5	MANE Select	c.775A>G	p.Ile259Val	missense	Exon 8 of 11	NP_058634.4	O95967
	EFEMP2	NR_037718.2		n.900A>G		non_coding_transcript_exon	Exon 8 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.775A>G	p.Ile259Val	missense	Exon 8 of 11	ENSP00000309953.6	O95967
	EFEMP2	ENST00000527969.1	TSL:1	n.1460A>G		non_coding_transcript_exon	Exon 4 of 4
	EFEMP2	ENST00000531972.5	TSL:1	n.775A>G		non_coding_transcript_exon	Exon 8 of 12	ENSP00000435295.1	O95967

Frequencies

GnomAD3 genomes AF: 0.906 AC: 137736 AN: 152094 Hom.: 63908 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.955

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.953

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.925

GnomAD2 exomes AF: 0.975 AC: 244922 AN: 251286 AF XY: 0.982

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.981

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.987

GnomAD4 exome AF: 0.989 AC: 1446057 AN: 1461640 Hom.: 717270 Cov.: 71 AF XY: 0.991 AC XY: 720498 AN XY: 727110

African (AFR) AF: 0.664 AC: 22239 AN: 33480

American (AMR) AF: 0.979 AC: 43767 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26101 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39699 AN: 39700

South Asian (SAS) AF: 0.999 AC: 86144 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53147 AN: 53170

Middle Eastern (MID) AF: 0.977 AC: 5636 AN: 5768

European-Non Finnish (NFE) AF: 0.999 AC: 1110395 AN: 1112010

Other (OTH) AF: 0.976 AC: 58929 AN: 60394

GnomAD4 genome AF: 0.905 AC: 137825 AN: 152212 Hom.: 63941 Cov.: 32 AF XY: 0.909 AC XY: 67608 AN XY: 74416

African (AFR) AF: 0.678 AC: 28124 AN: 41470

American (AMR) AF: 0.955 AC: 14611 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3467 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5179 AN: 5180

South Asian (SAS) AF: 0.999 AC: 4823 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10621 AN: 10624

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67862 AN: 68026

Other (OTH) AF: 0.926 AC: 1954 AN: 2110

Alfa AF: 0.959 Hom.: 173471

Bravo AF: 0.893

TwinsUK AF: 0.999 AC: 3704

ALSPAC AF: 0.998 AC: 3846

ESP6500AA AF: 0.692 AC: 3044

ESP6500EA AF: 0.998 AC: 8579

ExAC AF: 0.969 AC: 117696

Asia WGS AF: 0.984 AC: 3420 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.997

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Cutis laxa, autosomal recessive, type 1B (7)
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	-	Cutis laxa, autosomal recessive, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.1
DANN	Benign	0.77
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0000043	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.38	N
PhyloP100		0.14
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.30
ClinPred		0.00071	T
GERP RS		1.9
PromoterAI		0.077	Neutral
Varity_R		0.020
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs601314; hg19: chr11-65636053; COSMIC: COSV107334302; COSMIC: COSV107334302;