rs753429934

Positions:

• chr9-127824880-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_001114753.3(ENG):​c.911G>A​(p.Arg304Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.88

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a disulfide_bond (size 88) in uniprot entity EGLN_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_001114753.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.09487951).
• BP6: Variant 9-127824880-C-T is Benign according to our data. Variant chr9-127824880-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 528052.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.911G>A	p.Arg304Gln	missense_variant	7/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.911G>A	p.Arg304Gln	missense_variant	7/14		NP_000109.1
ENG	NM_001278138.2	c.365G>A	p.Arg122Gln	missense_variant	7/15		NP_001265067.1
ENG	NM_001406715.1	c.911G>A	p.Arg304Gln	missense_variant	7/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.911G>A	p.Arg304Gln	missense_variant	7/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.911G>A	p.Arg304Gln	missense_variant	7/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.365G>A	p.Arg122Gln	missense_variant	7/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152024 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249074 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1459998 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 726312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000930

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152024 Hom.: 0 Cov.: 28 AF XY: 0.0000539 AC XY: 4 AN XY: 74254

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 08, 2022

BP4 -

Hereditary hemorrhagic telangiectasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.6
DANN	Benign	0.89
DEOGEN2	Benign	0.28	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.94	N;.;N
REVEL	Benign	0.039
Sift	Benign	0.44	T;.;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.083	B;.;.
Vest4		0.074
MutPred		0.70		Loss of methylation at R304 (P = 0.0273);.;Loss of methylation at R304 (P = 0.0273);
MVP		0.50
MPC		0.25
ClinPred		0.033	T
GERP RS		-3.8
Varity_R		0.074
gMVP		0.37

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: rs753429934; hg19: chr9-130587159;