rs1554810373

Variant names:

• chr9-127825711-G-A
• rs1554810373
• NM_001114753.3:c.673C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-127825711-G-A
• chr9-127825711-G-C
• chr9-127825711-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001114753.3(ENG):​c.673C>T​(p.Pro225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P225Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21380967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.673C>T	p.Pro225Ser	missense_variant	Exon 5 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.673C>T	p.Pro225Ser	missense_variant	Exon 5 of 14		NP_000109.1
ENG	NM_001278138.2	c.127C>T	p.Pro43Ser	missense_variant	Exon 5 of 15		NP_001265067.1
ENG	NM_001406715.1	c.673C>T	p.Pro225Ser	missense_variant	Exon 5 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.673C>T	p.Pro225Ser	missense_variant	Exon 5 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1435834 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 712304

African (AFR) AF: 0.00 AC: 0 AN: 33174

American (AMR) AF: 0.00 AC: 0 AN: 43240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25276

East Asian (EAS) AF: 0.00 AC: 0 AN: 39100

South Asian (SAS) AF: 0.00 AC: 0 AN: 83856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4186

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102330

Other (OTH) AF: 0.00 AC: 0 AN: 59226

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace proline with serine at codon 225 of the ENG protein (p.(Pro225Ser)). The proline residue is moderately conserved with serine present in two mammals (100 vertebrates, UCSC), and is located in the C-terminal part of the OR1 domain. There is a moderate physicochemical difference between proline and serine. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1), and has not been reported in the relevant medical literature or databases. Multiple lines of computational evidence predict a benign effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;L
PhyloP100		2.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N;.;N
REVEL	Benign	0.019
Sift	Benign	0.47	T;.;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.21	B;.;.
Vest4		0.26
MutPred		0.37		Gain of MoRF binding (P = 0.0854);.;Gain of MoRF binding (P = 0.0854);
MVP		0.48
MPC		0.29
ClinPred		0.34	T
GERP RS		3.5
Varity_R		0.10
gMVP		0.52
Mutation Taster		=82/18	polymorphism

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: rs1554810373; hg19: chr9-130587990;