rs3739817

Variant names:

• chr9-127824409-G-A
• rs3739817
• NM_001114753.3:c.1029C>T

Variant summary

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

The NM_001114753.3(ENG):​c.1029C>T​(p.Thr343Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 1,613,948 control chromosomes in the GnomAD database, including 6,670 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (440 hom., cov: 30)
  • Exomes 𝑓: 0.086 (6230 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.80
• Publications: 25 publications found

Genes affected

ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ENG Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-127824409-G-A is Benign according to our data. Variant chr9-127824409-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114753.3. 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
	ENG	NM_001114753.3	MANE Select	c.1029C>T	p.Thr343Thr	synonymous	Exon 8 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1029C>T	p.Thr343Thr	synonymous	Exon 8 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.483C>T	p.Thr161Thr	synonymous	Exon 8 of 15	NP_001265067.1	F5GX88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.1029C>T	p.Thr343Thr	synonymous	Exon 8 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1029C>T	p.Thr343Thr	synonymous	Exon 8 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1029C>T	p.Thr343Thr	synonymous	Exon 8 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10922 AN: 152016 Hom.: 439 Cov.: 30

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0832

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0807

Gnomad OTH AF: 0.0680

GnomAD2 exomes AF: 0.0897 AC: 22536 AN: 251224 AF XY: 0.0949

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.0889

Gnomad ASJ exome AF: 0.0594

Gnomad EAS exome AF: 0.0279

Gnomad FIN exome AF: 0.0882

Gnomad NFE exome AF: 0.0821

Gnomad OTH exome AF: 0.0778

GnomAD4 exome AF: 0.0863 AC: 126174 AN: 1461814 Hom.: 6230 Cov.: 36 AF XY: 0.0895 AC XY: 65118 AN XY: 727216

African (AFR) AF: 0.0460 AC: 1539 AN: 33480

American (AMR) AF: 0.0870 AC: 3890 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0623 AC: 1627 AN: 26134

East Asian (EAS) AF: 0.0303 AC: 1201 AN: 39698

South Asian (SAS) AF: 0.190 AC: 16416 AN: 86256

European-Finnish (FIN) AF: 0.0902 AC: 4820 AN: 53408

Middle Eastern (MID) AF: 0.0869 AC: 501 AN: 5768

European-Non Finnish (NFE) AF: 0.0820 AC: 91201 AN: 1111960

Other (OTH) AF: 0.0824 AC: 4979 AN: 60390

GnomAD4 genome AF: 0.0718 AC: 10917 AN: 152134 Hom.: 440 Cov.: 30 AF XY: 0.0742 AC XY: 5519 AN XY: 74358

African (AFR) AF: 0.0483 AC: 2005 AN: 41514

American (AMR) AF: 0.0676 AC: 1033 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0602 AC: 209 AN: 3470

East Asian (EAS) AF: 0.0297 AC: 154 AN: 5184

South Asian (SAS) AF: 0.200 AC: 965 AN: 4816

European-Finnish (FIN) AF: 0.0832 AC: 880 AN: 10580

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0808 AC: 5490 AN: 67986

Other (OTH) AF: 0.0687 AC: 145 AN: 2110

Alfa AF: 0.0781 Hom.: 1582

Bravo AF: 0.0645

Asia WGS AF: 0.124 AC: 431 AN: 3478

EpiCase AF: 0.0770

EpiControl AF: 0.0729

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Telangiectasia, hereditary hemorrhagic, type 1 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hereditary hemorrhagic telangiectasia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		1.8
Mutation Taster		=100/0	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: rs3739817; hg19: chr9-130586688; COSMIC: COSV61227293; COSMIC: COSV61227293;