9-127854354-A-T

Variant names:

• chr9-127854354-A-T
• rs267606783
• NM_001114753.3:c.2T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_001114753.3(ENG):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENG NM_001114753.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 124 pathogenic variants. Next in-frame start position is after 183 codons. Genomic position: 127825837. Lost 0.277 part of the original CDS.
• PS1: Another start lost variant in NM_001114753.3 (ENG) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

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.2T>A	p.Met1?	start_lost	Exon 1 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.2T>A	p.Met1?	start_lost	Exon 1 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001406715.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 8	NP_001393644.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1436616 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 712480

African (AFR) AF: 0.00 AC: 0 AN: 32878

American (AMR) AF: 0.00 AC: 0 AN: 41096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25622

East Asian (EAS) AF: 0.00 AC: 0 AN: 38158

South Asian (SAS) AF: 0.00 AC: 0 AN: 82320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100222

Other (OTH) AF: 0.00 AC: 0 AN: 59344

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.034
Eigen_PC	Benign	0.073
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.94	T
PhyloP100		2.6
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.59	P
Vest4		0.93
MutPred		1.0		Loss of stability (P = 7e-04)
MVP		0.93
ClinPred		0.99	D
GERP RS		4.4
PromoterAI		-0.034	Neutral
Varity_R		0.90
gMVP		0.93
Mutation Taster		=3/197	disease causing

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: rs267606783; hg19: chr9-130616633;