rs633800

Variant names:

• chr11-65871248-G-A
• rs633800
• NM_016938.5:c.276C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-65871248-G-A
• chr11-65871248-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016938.5(EFEMP2):​c.276C>T​(p.His92His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,613,952 control chromosomes in the GnomAD database, including 195,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (14097 hom., cov: 32)
  • Exomes 𝑓: 0.49 (181745 hom.)
• Consequence: EFEMP2 NM_016938.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.87
• Publications: 29 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), Ambry Genetics, Genomics England PanelApp, ClinGen, G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-65871248-G-A is Benign according to our data. Variant chr11-65871248-G-A is described in ClinVar as Benign. ClinVar VariationId is 163326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.527 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.276C>T	p.His92His	synonymous	Exon 4 of 11	NP_058634.4	O95967
	EFEMP2	NR_037718.2		n.401C>T		non_coding_transcript_exon	Exon 4 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EFEMP2	ENST00000307998.11	TSL:1 MANE Select	c.276C>T	p.His92His	synonymous	Exon 4 of 11	ENSP00000309953.6	O95967
	EFEMP2	ENST00000531972.5	TSL:1	n.276C>T		non_coding_transcript_exon	Exon 4 of 12	ENSP00000435295.1	O95967
	EFEMP2	ENST00000907927.1		c.276C>T	p.His92His	synonymous	Exon 4 of 12	ENSP00000577986.1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60419 AN: 151990 Hom.: 14101 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.204

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: 0.447 AC: 112428 AN: 251410 AF XY: 0.468

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.199

Gnomad FIN exome AF: 0.569

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.490 AC: 716431 AN: 1461844 Hom.: 181745 Cov.: 65 AF XY: 0.495 AC XY: 360174 AN XY: 727230

African (AFR) AF: 0.151 AC: 5059 AN: 33480

American (AMR) AF: 0.292 AC: 13059 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12925 AN: 26136

East Asian (EAS) AF: 0.198 AC: 7860 AN: 39700

South Asian (SAS) AF: 0.565 AC: 48761 AN: 86258

European-Finnish (FIN) AF: 0.563 AC: 30094 AN: 53410

Middle Eastern (MID) AF: 0.584 AC: 3367 AN: 5768

European-Non Finnish (NFE) AF: 0.510 AC: 566932 AN: 1111976

Other (OTH) AF: 0.470 AC: 28374 AN: 60394

GnomAD4 genome AF: 0.397 AC: 60413 AN: 152108 Hom.: 14097 Cov.: 32 AF XY: 0.402 AC XY: 29868 AN XY: 74330

African (AFR) AF: 0.161 AC: 6703 AN: 41536

American (AMR) AF: 0.357 AC: 5452 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1723 AN: 3472

East Asian (EAS) AF: 0.203 AC: 1052 AN: 5174

South Asian (SAS) AF: 0.545 AC: 2626 AN: 4820

European-Finnish (FIN) AF: 0.582 AC: 6153 AN: 10568

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

European-Non Finnish (NFE) AF: 0.518 AC: 35220 AN: 67940

Other (OTH) AF: 0.438 AC: 924 AN: 2110

Alfa AF: 0.450 Hom.: 8418

Bravo AF: 0.364

Asia WGS AF: 0.376 AC: 1306 AN: 3478

EpiCase AF: 0.526

EpiControl AF: 0.527

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.7
DANN	Benign	0.94
PhyloP100		-1.9
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: rs633800; hg19: chr11-65638719; COSMIC: COSV57259926; COSMIC: COSV57259926;