rs142896669

Positions:

• chr9-127818173-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

The NM_001114753.3(ENG):​c.1633G>A​(p.Gly545Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000637 in 1,614,188 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. G545D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (2 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:5
• Conservation: PhyloP100: 4.33

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.060546517).
• BP6: Variant 9-127818173-C-T is Benign according to our data. Variant chr9-127818173-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237022.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000666 (973/1461876) while in subpopulation AMR AF= 0.00159 (71/44722). AF 95% confidence interval is 0.00129. There are 2 homozygotes in gnomad4_exome. There are 480 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1633G>A	p.Gly545Ser	missense_variant	12/15	ENST00000373203.9
LOC102723566	NR_136302.1	n.1378-138C>T		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1633G>A	p.Gly545Ser	missense_variant	12/14
ENG	NM_001278138.2	c.1087G>A	p.Gly363Ser	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1633G>A	p.Gly545Ser	missense_variant	12/15	1	NM_001114753.3	P2
	ENST00000439298.5	n.1378-138C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000521 AC: 131 AN: 251296 Hom.: 0 AF XY: 0.000456 AC XY: 62 AN XY: 135870

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000666 AC: 973 AN: 1461876 Hom.: 2 Cov.: 31 AF XY: 0.000660 AC XY: 480 AN XY: 727242

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000771

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000507 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 0.12% (rs142896669, 54/35,428 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Pulmonary hypertension, primary, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 2 probands, no segs in HGMD; ExAC: 0.2% (25/11560) Latino chromosomes -

Pulmonary arterial hypertension associated with congenital heart disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Wendy Chung Laboratory, Columbia University Medical Center

Jun 27, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2020

See Variant Classification Assertion Criteria. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary hemorrhagic telangiectasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	0.80	D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.057	T;.;D
Sift4G	Benign	0.095	T;T;D
Polyphen		1.0	D;.;.
Vest4		0.48
MVP		0.88
MPC		0.76
ClinPred		0.068	T
GERP RS		5.2
Varity_R		0.29
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: rs142896669; hg19: chr9-130580452; COSMIC: COSV61226765; COSMIC: COSV61226765;