rs770328302

Positions:

• chr9-127824928-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Moderate BP6_Moderate BS2

The NM_001114753.3(ENG):​c.863G>A​(p.Arg288His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,613,840 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.53

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 Likely_benign. Variant got -6 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.07159141).
• BP6: Variant 9-127824928-C-T is Benign according to our data. Variant chr9-127824928-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 458357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.863G>A	p.Arg288His	missense_variant	7/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.863G>A	p.Arg288His	missense_variant	7/14		NP_000109.1
ENG	NM_001278138.2	c.317G>A	p.Arg106His	missense_variant	7/15		NP_001265067.1
ENG	NM_001406715.1	c.863G>A	p.Arg288His	missense_variant	7/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.863G>A	p.Arg288His	missense_variant	7/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.863G>A	p.Arg288His	missense_variant	7/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.317G>A	p.Arg106His	missense_variant	7/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152028 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251356 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461812 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152028 Hom.: 0 Cov.: 28 AF XY: 0.0000135 AC XY: 1 AN XY: 74250

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.7
DANN	Benign	0.92
DEOGEN2	Benign	0.38	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	L;.;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.50	N;.;N
REVEL	Benign	0.061
Sift	Benign	0.097	T;.;T
Sift4G	Benign	0.098	T;T;T
Polyphen		0.97	D;.;.
Vest4		0.082
MutPred		0.27		Gain of ubiquitination at K285 (P = 0.0641);.;Gain of ubiquitination at K285 (P = 0.0641);
MVP		0.54
MPC		0.54
ClinPred		0.46	T
GERP RS		-8.4
Varity_R		0.086
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs770328302; hg19: chr9-130587207;