NM_001114753.3:c.219+25G>T

Variant names:

• chr9-127843069-C-A
• rs7847860
• NM_001114753.3:c.219+25G>T

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.219+25G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,582 control chromosomes in the GnomAD database, including 4,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (358 hom., cov: 31)
  • Exomes 𝑓: 0.069 (3823 hom.)
• Consequence: ENG NM_001114753.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.521
• Publications: 5 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-127843069-C-A is Benign according to our data. Variant chr9-127843069-C-A is described in ClinVar as Benign. ClinVar VariationId is 255144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 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.219+25G>T		intron	N/A	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.219+25G>T		intron	N/A	NP_000109.1	Q5T9B9
	ENG	NM_001278138.2		c.-328+25G>T		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.219+25G>T		intron	N/A	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.219+25G>T		intron	N/A	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.219+25G>T		intron	N/A	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes AF: 0.0633 AC: 9633 AN: 152200 Hom.: 355 Cov.: 31

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.0962

Gnomad EAS AF: 0.00384

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0667

Gnomad OTH AF: 0.0637

GnomAD2 exomes AF: 0.0640 AC: 16062 AN: 250950 AF XY: 0.0675

Gnomad AFR exome AF: 0.0641

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0955

Gnomad EAS exome AF: 0.00267

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0675

Gnomad OTH exome AF: 0.0685

GnomAD4 exome AF: 0.0685 AC: 100153 AN: 1461264 Hom.: 3823 Cov.: 32 AF XY: 0.0701 AC XY: 50941 AN XY: 726948

African (AFR) AF: 0.0632 AC: 2115 AN: 33466

American (AMR) AF: 0.0357 AC: 1596 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0911 AC: 2381 AN: 26134

East Asian (EAS) AF: 0.00458 AC: 182 AN: 39700

South Asian (SAS) AF: 0.114 AC: 9868 AN: 86228

European-Finnish (FIN) AF: 0.0550 AC: 2935 AN: 53344

Middle Eastern (MID) AF: 0.0715 AC: 391 AN: 5468

European-Non Finnish (NFE) AF: 0.0688 AC: 76496 AN: 1111876

Other (OTH) AF: 0.0694 AC: 4189 AN: 60332

GnomAD4 genome AF: 0.0633 AC: 9645 AN: 152318 Hom.: 358 Cov.: 31 AF XY: 0.0630 AC XY: 4690 AN XY: 74484

African (AFR) AF: 0.0643 AC: 2674 AN: 41558

American (AMR) AF: 0.0457 AC: 699 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0962 AC: 334 AN: 3472

East Asian (EAS) AF: 0.00385 AC: 20 AN: 5190

South Asian (SAS) AF: 0.113 AC: 547 AN: 4824

European-Finnish (FIN) AF: 0.0545 AC: 579 AN: 10626

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0667 AC: 4535 AN: 68024

Other (OTH) AF: 0.0626 AC: 132 AN: 2110

Alfa AF: 0.0661 Hom.: 80

Bravo AF: 0.0619

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Telangiectasia, hereditary hemorrhagic, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.8
DANN	Benign	0.67
PhyloP100		-0.52
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: rs7847860; hg19: chr9-130605348;