rs190129922

Variant names:

• chr9-127815191-G-A
• rs190129922
• NM_001114753.3:c.*491C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001114753.3(ENG):​c.*491C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000797 in 155,624 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: ENG NM_001114753.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.279

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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-127815191-G-A is Benign according to our data. Variant chr9-127815191-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 365077.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000802 (122/152060) while in subpopulation NFE AF = 0.00128 (87/67964). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.*491C>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.*726C>T		3_prime_UTR_variant	Exon 14 of 14		NP_000109.1
ENG	NM_001278138.2	c.*491C>T		3_prime_UTR_variant	Exon 15 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.*491C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes AF: 0.000803 AC: 122 AN: 151942 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000960

GnomAD4 exome AF: 0.000561 AC: 2 AN: 3564 Hom.: 0 Cov.: 0 AF XY: 0.000551 AC XY: 1 AN XY: 1816

African (AFR) AF: 0.00 AC: 0 AN: 44

American (AMR) AF: 0.00171 AC: 1 AN: 586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 34

East Asian (EAS) AF: 0.00 AC: 0 AN: 58

South Asian (SAS) AF: 0.00 AC: 0 AN: 156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 58

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.000402 AC: 1 AN: 2488

Other (OTH) AF: 0.00 AC: 0 AN: 136

GnomAD4 genome AF: 0.000802 AC: 122 AN: 152060 Hom.: 0 Cov.: 33 AF XY: 0.000767 AC XY: 57 AN XY: 74308

African (AFR) AF: 0.000145 AC: 6 AN: 41522

American (AMR) AF: 0.000589 AC: 9 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 67964

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000608

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.65
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

dbSNP: rs190129922; hg19: chr9-130577470;