rs780987528

chr9-127825795-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001114753.3(ENG):c.589C>T(p.Arg197Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000439 in 1,595,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R197Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.138

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07395631).
• BP6: Variant 9-127825795-G-A is Benign according to our data. Variant chr9-127825795-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407122.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.589C>T	p.Arg197Trp	missense_variant	5/15	ENST00000373203.9
ENG	NM_000118.4	c.589C>T	p.Arg197Trp	missense_variant	5/14
ENG	NM_001278138.2	c.43C>T	p.Arg15Trp	missense_variant	5/15
ENG	NM_001406715.1	c.589C>T	p.Arg197Trp	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.589C>T	p.Arg197Trp	missense_variant	5/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.589C>T	p.Arg197Trp	missense_variant	5/14	1		A2
ENG	ENST00000480266.6	c.43C>T	p.Arg15Trp	missense_variant	5/15	2
ENG	ENST00000462196.1	n.489C>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 5 AN: 209562 Hom.: 0 AF XY: 0.0000349 AC XY: 4 AN XY: 114578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000369

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.0000457 AC: 66 AN: 1443160 Hom.: 0 Cov.: 34 AF XY: 0.0000433 AC XY: 31 AN XY: 716174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000489

Gnomad4 OTH exome AF: 0.0000839

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000583 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000417 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 14, 2022

- -

Hereditary hemorrhagic telangiectasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.31	T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.074	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.018
Sift	Benign	0.11	T;.;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.0040	B;.;.
Vest4		0.15
MVP		0.19
MPC		0.22
ClinPred		0.070	T
GERP RS		-1.5
Varity_R		0.23
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs780987528; hg19: chr9-130588074; COSMIC: COSV100785347; COSMIC: COSV100785347;