rs115675061

chr9-127829813-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001114753.3(ENG):c.234G>A(p.Leu78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,614,080 control chromosomes in the GnomAD database, including 2 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. L78L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000085 (1 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 9-127829813-C-T is Benign according to our data. Variant chr9-127829813-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 528074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127829813-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000749 (114/152278) while in subpopulation AFR AF= 0.0026 (108/41562). AF 95% confidence interval is 0.0022. There are 1 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.234G>A	p.Leu78=	synonymous_variant	3/15	ENST00000373203.9
ENG	NM_000118.4	c.234G>A	p.Leu78=	synonymous_variant	3/14
ENG	NM_001406715.1	c.234G>A	p.Leu78=	synonymous_variant	3/8
ENG	NM_001278138.2	c.-313G>A		5_prime_UTR_variant	3/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.234G>A	p.Leu78=	synonymous_variant	3/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.234G>A	p.Leu78=	synonymous_variant	3/14	1		A2
ENG	ENST00000480266.6	c.-313G>A		5_prime_UTR_variant	3/15	2
ENG	ENST00000462196.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152160 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 251332 Hom.: 1 AF XY: 0.000199 AC XY: 27 AN XY: 135852

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461802 Hom.: 1 Cov.: 31 AF XY: 0.0000770 AC XY: 56 AN XY: 727198

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152278 Hom.: 1 Cov.: 31 AF XY: 0.000833 AC XY: 62 AN XY: 74456

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000786

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 17, 2017

- -

Hereditary hemorrhagic telangiectasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2022

This alteration is classified as likely 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	-0.41
Cadd	Benign	9.5
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs115675061; hg19: chr9-130592092;