NM_001114753.3:c.1794T>C

Variant names:

• chr9-127816001-A-G
• rs41358947
• NM_001114753.3:c.1794T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001114753.3(ENG):​c.1794T>C​(p.Gly598Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,610,468 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene ENG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.014 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (110 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.01
• Publications: 1 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

ENSG00000225032 (HGNC:):

ACMG classification

Specifications for ENG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 9-127816001-A-G is Benign according to our data. Variant chr9-127816001-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0144 (2200/152302) while in subpopulation AFR AF = 0.0417 (1733/41554). AF 95% confidence interval is 0.0401. There are 44 homozygotes in GnomAd4. There are 1084 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2200 AD gene.

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.1794T>C	p.Gly598Gly	synonymous	Exon 14 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1794T>C	p.Gly598Gly	synonymous	Exon 14 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.1248T>C	p.Gly416Gly	synonymous	Exon 14 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.1794T>C	p.Gly598Gly	synonymous	Exon 14 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1794T>C	p.Gly598Gly	synonymous	Exon 14 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1794T>C	p.Gly598Gly	synonymous	Exon 14 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2200 AN: 152184 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0418

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00804

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00832 AC: 2019 AN: 242772 AF XY: 0.00885

Gnomad AFR exome AF: 0.0431

Gnomad AMR exome AF: 0.00343

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000388

Gnomad FIN exome AF: 0.0000494

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00485 AC: 7066 AN: 1458166 Hom.: 110 Cov.: 31 AF XY: 0.00562 AC XY: 4072 AN XY: 725040

African (AFR) AF: 0.0448 AC: 1498 AN: 33454

American (AMR) AF: 0.00368 AC: 163 AN: 44276

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26016

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39608

South Asian (SAS) AF: 0.0341 AC: 2910 AN: 85454

European-Finnish (FIN) AF: 0.000114 AC: 6 AN: 52598

Middle Eastern (MID) AF: 0.00318 AC: 18 AN: 5664

European-Non Finnish (NFE) AF: 0.00187 AC: 2076 AN: 1110876

Other (OTH) AF: 0.00639 AC: 385 AN: 60220

GnomAD4 genome AF: 0.0144 AC: 2200 AN: 152302 Hom.: 44 Cov.: 33 AF XY: 0.0146 AC XY: 1084 AN XY: 74488

African (AFR) AF: 0.0417 AC: 1733 AN: 41554

American (AMR) AF: 0.00803 AC: 123 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0366 AC: 177 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68008

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00718 Hom.: 8

Bravo AF: 0.0162

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	2	Telangiectasia, hereditary hemorrhagic, type 1 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	5.3
DANN	Benign	0.65
PhyloP100		-1.0
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41358947; hg19: chr9-130578280;