9-127825293-T-C

Variant names:

• chr9-127825293-T-C
• rs377377549
• NM_001114753.3:c.754A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001114753.3(ENG):​c.754A>G​(p.Ile252Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.793

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 Uncertain_significance. Variant got 4 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
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.754A>G	p.Ile252Val	missense_variant	Exon 6 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.754A>G	p.Ile252Val	missense_variant	Exon 6 of 14		NP_000109.1
ENG	NM_001278138.2	c.208A>G	p.Ile70Val	missense_variant	Exon 6 of 15		NP_001265067.1
ENG	NM_001406715.1	c.754A>G	p.Ile252Val	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.754A>G	p.Ile252Val	missense_variant	Exon 6 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.754A>G	p.Ile252Val	missense_variant	Exon 6 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.208A>G	p.Ile70Val	missense_variant	Exon 6 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726978

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T;T;.
Eigen	Benign	0.051
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.73	N;.;N
REVEL	Benign	0.19
Sift	Benign	0.097	T;.;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.98	D;.;.
Vest4		0.39
MutPred		0.69		Gain of catalytic residue at I252 (P = 0.252);.;Gain of catalytic residue at I252 (P = 0.252);
MVP		0.59
MPC		0.66
ClinPred		0.42	T
GERP RS		3.4
Varity_R		0.14
gMVP		0.45

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: rs377377549; hg19: chr9-130587572;