9-127825239-G-T

Variant names:

• chr9-127825239-G-T
• NM_001114753.3:c.808C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001114753.3(ENG):​c.808C>A​(p.Gln270Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.87

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a disulfide_bond (size 88) in uniprot entity EGLN_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27389324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.808C>A	p.Gln270Lys	missense_variant	Exon 6 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.808C>A	p.Gln270Lys	missense_variant	Exon 6 of 14		NP_000109.1
ENG	NM_001278138.2	c.262C>A	p.Gln88Lys	missense_variant	Exon 6 of 15		NP_001265067.1
ENG	NM_001406715.1	c.808C>A	p.Gln270Lys	missense_variant	Exon 6 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.808C>A	p.Gln270Lys	missense_variant	Exon 6 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.808C>A	p.Gln270Lys	missense_variant	Exon 6 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.262C>A	p.Gln88Lys	missense_variant	Exon 6 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461698 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Uncertain:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 270 of the ENG protein (p.Gln270Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ENG-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.35	T;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N;.;N
REVEL	Benign	0.062
Sift	Benign	0.25	T;.;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.022	B;.;.
Vest4		0.36
MutPred		0.49		Gain of ubiquitination at Q270 (P = 0.0337);.;Gain of ubiquitination at Q270 (P = 0.0337);
MVP		0.53
MPC		0.30
ClinPred		0.24	T
GERP RS		3.7
Varity_R		0.55
gMVP		0.69

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130587518;