rs4836585

Variant names:

• chr9-127850104-C-A
• rs4836585
• NM_001114753.3:c.67+4185G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001114753.3(ENG):​c.67+4185G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.749 in 152,114 control chromosomes in the GnomAD database, including 45,894 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (45894 hom., cov: 33)
• Consequence: ENG NM_001114753.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252
• Publications: 3 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.67+4185G>T		intron_variant	Intron 1 of 14	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.67+4185G>T		intron_variant	Intron 1 of 13		NP_000109.1
ENG	NM_001406715.1	c.67+4185G>T		intron_variant	Intron 1 of 7		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.67+4185G>T		intron_variant	Intron 1 of 14	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes AF: 0.750 AC: 113951 AN: 151996 Hom.: 45884 Cov.: 33

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.924

Gnomad SAS AF: 0.893

Gnomad FIN AF: 0.913

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.877

Gnomad OTH AF: 0.767

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.749 AC: 113994 AN: 152114 Hom.: 45894 Cov.: 33 AF XY: 0.756 AC XY: 56185 AN XY: 74344

African (AFR) AF: 0.426 AC: 17669 AN: 41452

American (AMR) AF: 0.818 AC: 12494 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 3002 AN: 3470

East Asian (EAS) AF: 0.924 AC: 4788 AN: 5180

South Asian (SAS) AF: 0.893 AC: 4306 AN: 4822

European-Finnish (FIN) AF: 0.913 AC: 9676 AN: 10602

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.877 AC: 59609 AN: 67996

Other (OTH) AF: 0.768 AC: 1620 AN: 2110

Alfa AF: 0.823 Hom.: 68919

Bravo AF: 0.730

Asia WGS AF: 0.865 AC: 3009 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4836585; hg19: chr9-130612383;