9-127816068-C-T

Position:

chr9-127816068-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001114753.3(ENG):c.1742-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000076 in 1,605,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

ENG
NM_001114753.3 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0970

Variant links:

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]

ENG links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 9-127816068-C-T is Benign according to our data. Variant chr9-127816068-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504728.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000778 (113/1453332) while in subpopulation EAS AF= 0.00241 (95/39484). AF 95% confidence interval is 0.00201. There are 0 homozygotes in gnomad4_exome. There are 56 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
ENG	NM_001114753.3 linkuse as main transcript	c.1742-15G>A	splice_polypyrimidine_tract_variant, intron_variant		ENST00000373203.9	NP_001108225.1
LOC102723566	NR_136302.1 linkuse as main transcript	n.3C>T	non_coding_transcript_exon_variant	1/6
ENG	NM_000118.4 linkuse as main transcript	c.1742-15G>A	splice_polypyrimidine_tract_variant, intron_variant			NP_000109.1
ENG	NM_001278138.2 linkuse as main transcript	c.1196-15G>A	splice_polypyrimidine_tract_variant, intron_variant			NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.1742-15G>A	splice_polypyrimidine_tract_variant, intron_variant		1	NM_001114753.3	ENSP00000362299	P2	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.1742-15G>A	splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000341917	A2	P17813-2
	ENST00000439298.5 linkuse as main transcript	n.3C>T	non_coding_transcript_exon_variant	1/6	2
ENG	ENST00000480266.6 linkuse as main transcript	c.1196-15G>A	splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000479015

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000468

AC:

AN:

234800

Hom.:

AF XY:

0.0000392

AC XY:

AN XY:

127608

show subpopulations

Gnomad AFR exome

AF:

0.0000690

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000397

Gnomad SAS exome

AF:

0.0000344

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000778

AC:

113

AN:

1453332

Hom.:

Cov.:

AF XY:

0.0000775

AC XY:

AN XY:

722426

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00241

Gnomad4 SAS exome

AF:

0.0000588

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000901

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2017

Variant classified as Uncertain Significance - Favor Benign. The c.1742-15G>A va riant in ENG has not been previously reported in individuals with pulmonary hype rtension, but has been identified in 8/18138 East Asian chromosomes by the Genom e Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201678 228). This variant is located in the 3' splice region. Computational tools do no t suggest an impact to splicing. However, this information is not predictive eno ugh to rule out pathogenicity. In summary, while the clinical significance of th e c.1742-15G>A variant is uncertain, these data suggest that it is more likely t o be benign. ACMG/AMP Criteria applied: BP4 (Richards 2015). -

Hereditary hemorrhagic telangiectasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.8

DANN

Benign

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over