rs1060504230

Variant names:

• chr9-127843133-GG-TT
• rs1060504230
• NM_001114753.3:c.179_180delCCinsAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PM1 PM2 BP6_Very_Strong

The NM_001114753.3(ENG):​c.179_180delCCinsAA​(p.Ala60Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A60D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.05

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 9-127843133-GG-TT is Benign according to our data. Variant chr9-127843133-GG-TT is described in ClinVar as [Likely_benign]. Clinvar id is 414311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.179_180delCCinsAA	p.Ala60Glu	missense_variant		ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.179_180delCCinsAA	p.Ala60Glu	missense_variant			NP_000109.1
ENG	NM_001406715.1	c.179_180delCCinsAA	p.Ala60Glu	missense_variant			NP_001393644.1
ENG	NM_001278138.2	c.-368_-367delCCinsAA		5_prime_UTR_variant	Exon 2 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.179_180delCCinsAA	p.Ala60Glu	missense_variant		1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.179_180delCCinsAA	p.Ala60Glu	missense_variant		1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-368_-367delCCinsAA		5_prime_UTR_variant	Exon 2 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Oct 22, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Cardiovascular phenotype Benign:1

Aug 19, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060504230; hg19: chr9-130605412;