rs747481834

Variant names:

• chr9-127843201-C-T
• rs747481834
• NM_001114753.3:c.112G>A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001114753.3(ENG):​c.112G>A​(p.Glu38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.642

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054531604).
• BP6: Variant 9-127843201-C-T is Benign according to our data. Variant chr9-127843201-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 568326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.112G>A	p.Glu38Lys	missense_variant	Exon 2 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.112G>A	p.Glu38Lys	missense_variant	Exon 2 of 14		NP_000109.1
ENG	NM_001406715.1	c.112G>A	p.Glu38Lys	missense_variant	Exon 2 of 8		NP_001393644.1
ENG	NM_001278138.2	c.-435G>A		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.112G>A	p.Glu38Lys	missense_variant	Exon 2 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.112G>A	p.Glu38Lys	missense_variant	Exon 2 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-435G>A		5_prime_UTR_variant	Exon 2 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251458 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Benign:1

Mar 26, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Sep 17, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.018
Sift	Benign	0.25	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.024	B;.
Vest4		0.14
MutPred		0.26		Gain of methylation at E38 (P = 0.0075);Gain of methylation at E38 (P = 0.0075);
MVP		0.46
MPC		0.24
ClinPred		0.039	T
GERP RS		-2.6
Varity_R		0.27
gMVP		0.43

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

Other links and lift over

dbSNP: rs747481834; hg19: chr9-130605480; COSMIC: COSV100785301; COSMIC: COSV100785301;