9-127818770-T-C

Position:

• chr9-127818770-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001114753.3(ENG):​c.1374A>G​(p.Pro458=) 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (13 hom., cov: 32)
  • Exomes 𝑓: 0.010 (115 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.79

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 213202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127818770-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1315 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1374A>G	p.Pro458=	synonymous_variant	11/15	ENST00000373203.9	NP_001108225.1
LOC102723566	NR_136302.1	n.1568+59T>C		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1374A>G	p.Pro458=	synonymous_variant	11/14		NP_000109.1
ENG	NM_001278138.2	c.828A>G	p.Pro276=	synonymous_variant	11/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1374A>G	p.Pro458=	synonymous_variant	11/15	1	NM_001114753.3	ENSP00000362299	P2
	ENST00000439298.5	n.1568+59T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1316 AN: 152038 Hom.: 13 Cov.: 32

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

GnomAD3 exomes AF: 0.0102 AC: 2553 AN: 251484 Hom.: 23 AF XY: 0.0102 AC XY: 1387 AN XY: 135914

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 SAS exome AF: 0.00657

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.: 31 AF XY: 0.0103 AC XY: 7511 AN XY: 727226

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00642

Gnomad4 FIN exome AF: 0.0309

Gnomad4 NFE exome AF: 0.0111

Gnomad4 OTH exome AF: 0.00833

GnomAD4 genome AF: 0.00864 AC: 1315 AN: 152156 Hom.: 13 Cov.: 32 AF XY: 0.00976 AC XY: 726 AN XY: 74420

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00851

Gnomad4 FIN AF: 0.0317

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.0104 Hom.: 3

Bravo AF: 0.00693

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00921

EpiControl AF: 0.00853

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ENG: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Telangiectasia, hereditary hemorrhagic, type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Hereditary hemorrhagic telangiectasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.49

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

LitVar

Other links and lift over

dbSNP: rs34828244; hg19: chr9-130581049;