rs762569294

chr9-127825314-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.733G>A(p.Gly245Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,611,244 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin Lovd.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.115

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_001114753.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.09449831).
• BP6: Variant 9-127825314-C-T is Benign according to our data. Variant chr9-127825314-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 582982.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.733G>A	p.Gly245Arg	missense_variant	6/15	ENST00000373203.9
ENG	NM_000118.4	c.733G>A	p.Gly245Arg	missense_variant	6/14
ENG	NM_001278138.2	c.187G>A	p.Gly63Arg	missense_variant	6/15
ENG	NM_001406715.1	c.733G>A	p.Gly245Arg	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.733G>A	p.Gly245Arg	missense_variant	6/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.733G>A	p.Gly245Arg	missense_variant	6/14	1		A2
ENG	ENST00000480266.6	c.187G>A	p.Gly63Arg	missense_variant	6/15	2

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 4 AN: 149910 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249994 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461216 Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25 AN XY: 726906

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000267 AC: 4 AN: 150028 Hom.: 0 Cov.: 26 AF XY: 0.0000410 AC XY: 3 AN XY: 73120

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000330 AC: 4

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

Invitae

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	16
Dann	Benign	0.65
DEOGEN2	Benign	0.25	T;T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.094	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.029
Sift	Benign	0.28	T;.;T
Sift4G	Benign	0.81	T;T;T
Polyphen		0.45	B;.;.
Vest4		0.21
MutPred		0.43		Gain of solvent accessibility (P = 0.0097);.;Gain of solvent accessibility (P = 0.0097);
MVP		0.45
MPC		0.30
ClinPred		0.039	T
GERP RS		0.36
Varity_R		0.17
gMVP		0.64

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: rs762569294; hg19: chr9-130587593; COSMIC: COSV61228215; COSMIC: COSV61228215;