rs548424658

Variant names:

• chr9-127825788-C-A
• rs548424658
• NM_001114753.3:c.596G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-127825788-C-A
• chr9-127825788-C-G
• chr9-127825788-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001114753.3(ENG):​c.596G>T​(p.Arg199Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. R199C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064054966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.596G>T	p.Arg199Leu	missense_variant	Exon 5 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.596G>T	p.Arg199Leu	missense_variant	Exon 5 of 14		NP_000109.1
ENG	NM_001278138.2	c.50G>T	p.Arg17Leu	missense_variant	Exon 5 of 15		NP_001265067.1
ENG	NM_001406715.1	c.596G>T	p.Arg199Leu	missense_variant	Exon 5 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.596G>T	p.Arg199Leu	missense_variant	Exon 5 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.596G>T	p.Arg199Leu	missense_variant	Exon 5 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.50G>T	p.Arg17Leu	missense_variant	Exon 5 of 15	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.*1G>T		downstream_gene_variant		3		ENSP00000519251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441976 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 715584

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000253 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.14
DANN	Benign	0.76
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.25	N;.;N
REVEL	Benign	0.012
Sift	Benign	0.26	T;.;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0070	B;.;.
Vest4		0.061
MVP		0.23
MPC		0.27
ClinPred		0.049	T
GERP RS		-4.7
Varity_R		0.098
gMVP		0.40

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: rs548424658; hg19: chr9-130588067;