9-127825259-A-G

Variant names:

• chr9-127825259-A-G
• rs1085307431
• NM_001114753.3:c.788T>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong

The NM_001114753.3(ENG):​c.788T>C​(p.Ile263Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 150,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I263S) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 27)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17

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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_001114753.3 (ENG) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a strand (size 8) in uniprot entity EGLN_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001114753.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.788T>C	p.Ile263Thr	missense_variant	Exon 6 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.788T>C	p.Ile263Thr	missense_variant	Exon 6 of 14		NP_000109.1
ENG	NM_001278138.2	c.242T>C	p.Ile81Thr	missense_variant	Exon 6 of 15		NP_001265067.1
ENG	NM_001406715.1	c.788T>C	p.Ile263Thr	missense_variant	Exon 6 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.788T>C	p.Ile263Thr	missense_variant	Exon 6 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.788T>C	p.Ile263Thr	missense_variant	Exon 6 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.242T>C	p.Ile81Thr	missense_variant	Exon 6 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150436 Hom.: 0 Cov.: 27

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150436 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 73278

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.94
MutPred		0.86		Loss of stability (P = 0.0021);.;Loss of stability (P = 0.0021);
MVP		0.91
MPC		0.91
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.87

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: rs1085307431; hg19: chr9-130587538;