Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001114753.3(ENG):c.1374A>G(p.Pro458Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,002 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P458P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0086 ( 13 hom., cov: 32)

Exomes 𝑓: 0.010 ( 115 hom. )

Consequence

ENG
NM_001114753.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.79

Publications

4 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
hereditary hemorrhagic telangiectasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
juvenile polyposis syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENG links:

ENSG00000225032 (HGNC:):

ENSG00000225032 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 9-127818770-T-C is Benign according to our data. Variant chr9-127818770-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.79 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00864 (1315/152156) while in subpopulation NFE AF = 0.0112 (760/67994). AF 95% confidence interval is 0.0105. There are 13 homozygotes in GnomAd4. There are 726 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1315 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ENG	NM_001114753.3	MANE Select	c.1374A>G	p.Pro458Pro	synonymous	Exon 11 of 15	NP_001108225.1
ENG	NM_000118.4		c.1374A>G	p.Pro458Pro	synonymous	Exon 11 of 14	NP_000109.1
ENG	NM_001278138.2		c.828A>G	p.Pro276Pro	synonymous	Exon 11 of 15	NP_001265067.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ENG	ENST00000373203.9	TSL:1 MANE Select	c.1374A>G	p.Pro458Pro	synonymous	Exon 11 of 15	ENSP00000362299.4
ENG	ENST00000344849.5	TSL:1	c.1374A>G	p.Pro458Pro	synonymous	Exon 11 of 14	ENSP00000341917.3
ENG	ENST00000714047.1		c.1374A>G	p.Pro458Pro	synonymous	Exon 11 of 15	ENSP00000519338.1

Frequencies

GnomAD3 genomes

AF:

0.00866

AC:

1316

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.0317

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0112

Gnomad OTH

AF:

0.00767

GnomAD2 exomes

AF:

0.0102

AC:

2553

AN:

251484

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00280

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0320

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0105

AC:

15324

AN:

1461846

Hom.:

115

Cov.:

AF XY:

0.0103

AC XY:

7511

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00167

AC:

AN:

33480

American (AMR)

AF:

0.00306

AC:

137

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00367

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00642

AC:

554

AN:

86258

European-Finnish (FIN)

AF:

0.0309

AC:

1649

AN:

53410

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0111

AC:

12290

AN:

1111986

Other (OTH)

AF:

0.00833

AC:

503

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

963

1926

2889

3852

4815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

434

868

1302

1736

2170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00864

AC:

1315

AN:

152156

Hom.:

Cov.:

AF XY:

0.00976

AC XY:

726

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41520

American (AMR)

AF:

0.00537

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.000388

AC:

AN:

5160

South Asian (SAS)

AF:

0.00851

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0317

AC:

336

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0112

AC:

760

AN:

67994

Other (OTH)

AF:

0.00759

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.00693

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00921

EpiControl

AF:

0.00853

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Telangiectasia, hereditary hemorrhagic, type 1 (2)

Cardiovascular phenotype (1)

Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.7

(source)

DANN

Benign

0.49

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001114753.3:c.1374A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over