9-127816125-A-G

Variant names:

• chr9-127816125-A-G
• rs10760503
• NM_001114753.3:c.1742-72T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001114753.3(ENG):​c.1742-72T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,549,808 control chromosomes in the GnomAD database, including 156,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15457 hom., cov: 33)
  • Exomes 𝑓: 0.45 (140843 hom.)
• Consequence: ENG NM_001114753.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.696
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000225032 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-127816125-A-G is Benign according to our data. Variant chr9-127816125-A-G is described in ClinVar as Benign. ClinVar VariationId is 672484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114753.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	NM_001114753.3	MANE Select	c.1742-72T>C		intron	N/A	NP_001108225.1
	LOC102723566	NR_136302.1		n.60A>G		non_coding_transcript_exon	Exon 1 of 6
	ENG	NM_000118.4		c.1742-72T>C		intron	N/A	NP_000109.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.1742-72T>C		intron	N/A	ENSP00000362299.4
	ENG	ENST00000344849.5	TSL:1	c.1742-72T>C		intron	N/A	ENSP00000341917.3
	ENSG00000225032	ENST00000439298.5	TSL:2	n.60A>G		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68111 AN: 151896 Hom.: 15444 Cov.: 33

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.471

GnomAD4 exome AF: 0.446 AC: 622841 AN: 1397794 Hom.: 140843 Cov.: 28 AF XY: 0.443 AC XY: 306689 AN XY: 691566

African (AFR) AF: 0.431 AC: 13876 AN: 32162

American (AMR) AF: 0.480 AC: 17700 AN: 36860

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 10904 AN: 25156

East Asian (EAS) AF: 0.688 AC: 25510 AN: 37102

South Asian (SAS) AF: 0.390 AC: 31196 AN: 79934

European-Finnish (FIN) AF: 0.382 AC: 18564 AN: 48602

Middle Eastern (MID) AF: 0.422 AC: 1729 AN: 4096

European-Non Finnish (NFE) AF: 0.444 AC: 477395 AN: 1075976

Other (OTH) AF: 0.448 AC: 25967 AN: 57906

GnomAD4 genome AF: 0.448 AC: 68168 AN: 152014 Hom.: 15457 Cov.: 33 AF XY: 0.446 AC XY: 33110 AN XY: 74314

African (AFR) AF: 0.440 AC: 18256 AN: 41474

American (AMR) AF: 0.473 AC: 7232 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1559 AN: 3460

East Asian (EAS) AF: 0.693 AC: 3580 AN: 5166

South Asian (SAS) AF: 0.393 AC: 1898 AN: 4824

European-Finnish (FIN) AF: 0.377 AC: 3991 AN: 10576

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30047 AN: 67918

Other (OTH) AF: 0.469 AC: 993 AN: 2116

Alfa AF: 0.438 Hom.: 17564

Bravo AF: 0.461

Asia WGS AF: 0.518 AC: 1804 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.8
DANN	Benign	0.24
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10760503; hg19: chr9-130578404; COSMIC: COSV61227320; COSMIC: COSV61227320;