9-127826641-G-C

Variant names:

• chr9-127826641-G-C
• NM_001114753.3:c.392C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001114753.3(ENG):​c.392C>G​(p.Pro131Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P131L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0560

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2115083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.392C>G	p.Pro131Arg	missense_variant	Exon 4 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.392C>G	p.Pro131Arg	missense_variant	Exon 4 of 14		NP_000109.1
ENG	NM_001406715.1	c.392C>G	p.Pro131Arg	missense_variant	Exon 4 of 8		NP_001393644.1
ENG	NM_001278138.2	c.-155C>G		5_prime_UTR_variant	Exon 4 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.392C>G	p.Pro131Arg	missense_variant	Exon 4 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.392C>G	p.Pro131Arg	missense_variant	Exon 4 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-155C>G		5_prime_UTR_variant	Exon 4 of 15	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.292C>G		non_coding_transcript_exon_variant	Exon 3 of 4	3		ENSP00000519251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461634 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.5
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.094
Sift	Benign	0.077	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.95	P;.
Vest4		0.21
MutPred		0.39		Loss of catalytic residue at P130 (P = 0.016);Loss of catalytic residue at P130 (P = 0.016);
MVP		0.54
MPC		0.43
ClinPred		0.42	T
GERP RS		-1.9
Varity_R		0.28
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130588920;