9-127817814-T-C

Variant names:

• chr9-127817814-T-C
• rs10987746
• NM_001114753.3:c.1686+306A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001114753.3(ENG):​c.1686+306A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 514,410 control chromosomes in the GnomAD database, including 58,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18116 hom., cov: 32)
  • Exomes 𝑓: 0.46 (40417 hom.)
• Consequence: ENG NM_001114753.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.33
• Publications: 15 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 9-127817814-T-C is Benign according to our data. Variant chr9-127817814-T-C is described in ClinVar as Benign. ClinVar VariationId is 1275607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

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.1686+306A>G		intron	N/A	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1686+306A>G		intron	N/A	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.1140+306A>G		intron	N/A	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.1686+306A>G		intron	N/A	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1686+306A>G		intron	N/A	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1686+306A>G		intron	N/A	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73626 AN: 151832 Hom.: 18100 Cov.: 32

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.510

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.502

GnomAD4 exome AF: 0.465 AC: 168418 AN: 362458 Hom.: 40417 Cov.: 3 AF XY: 0.459 AC XY: 87215 AN XY: 189994

African (AFR) AF: 0.547 AC: 5830 AN: 10658

American (AMR) AF: 0.488 AC: 7713 AN: 15812

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 4938 AN: 11220

East Asian (EAS) AF: 0.687 AC: 16310 AN: 23724

South Asian (SAS) AF: 0.395 AC: 17241 AN: 43628

European-Finnish (FIN) AF: 0.411 AC: 8811 AN: 21430

Middle Eastern (MID) AF: 0.437 AC: 690 AN: 1578

European-Non Finnish (NFE) AF: 0.454 AC: 96994 AN: 213450

Other (OTH) AF: 0.472 AC: 9891 AN: 20958

GnomAD4 genome AF: 0.485 AC: 73690 AN: 151952 Hom.: 18116 Cov.: 32 AF XY: 0.482 AC XY: 35791 AN XY: 74304

African (AFR) AF: 0.541 AC: 22425 AN: 41448

American (AMR) AF: 0.489 AC: 7468 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1572 AN: 3456

East Asian (EAS) AF: 0.690 AC: 3560 AN: 5156

South Asian (SAS) AF: 0.400 AC: 1926 AN: 4820

European-Finnish (FIN) AF: 0.407 AC: 4301 AN: 10560

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30769 AN: 67928

Other (OTH) AF: 0.500 AC: 1054 AN: 2108

Alfa AF: 0.467 Hom.: 52853

Bravo AF: 0.500

Asia WGS AF: 0.523 AC: 1821 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.21
DANN	Benign	0.32
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs10987746; hg19: chr9-130580093;