rs1060501418

Variant names:

• chr9-127854355-T-C
• rs1060501418
• NM_001114753.3:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-127854355-T-C
• chr9-127854355-T-G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000696 in 1,436,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.63
• Publications: 11 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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: Pathogenic. The variant received 20 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
• PP5: Variant 9-127854355-T-C is Pathogenic according to our data. Variant chr9-127854355-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 407131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1A>G	p.Met1?	start_lost	Exon 1 of 15	NP_001108225.1	P17813-1
	ENG	NM_000118.4		c.1A>G	p.Met1?	start_lost	Exon 1 of 14	NP_000109.1	Q5T9B9
	ENG	NM_001406715.1		c.1A>G	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.1A>G	p.Met1?	start_lost	Exon 1 of 15	ENSP00000362299.4	P17813-1
	ENG	ENST00000344849.5	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 14	ENSP00000341917.3	P17813-2
	ENG	ENST00000714047.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 15	ENSP00000519338.1	A0AAQ5BHC4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436158 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 712250

African (AFR) AF: 0.00 AC: 0 AN: 32864

American (AMR) AF: 0.00 AC: 0 AN: 41018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 38132

South Asian (SAS) AF: 0.00 AC: 0 AN: 82266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099984

Other (OTH) AF: 0.00 AC: 0 AN: 59326

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Telangiectasia, hereditary hemorrhagic, type 1 (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hereditary hemorrhagic telangiectasia (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.74	T
PhyloP100		3.6
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.96
MutPred		1.0		Loss of stability (P = 0.0961)
MVP		0.92
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		-0.15	Neutral
Varity_R		0.90
gMVP		0.83
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs1060501418; hg19: chr9-130616634;