9-127824305-G-T

Variant names:

• chr9-127824305-G-T
• NM_001114753.3:c.1133C>A

Variant summary

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

The NM_001114753.3(ENG):​c.1133C>A​(p.Ala378Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A378A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 missense, splice_region
• Scores: Splicing: ADA: 0.00004104
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.236

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=0.055515945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1133C>A	p.Ala378Glu	missense_variant, splice_region_variant	Exon 8 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_001406715.1	c.1133C>A	p.Ala378Glu	missense_variant	Exon 8 of 8		NP_001393644.1
ENG	NM_000118.4	c.1133C>A	p.Ala378Glu	missense_variant, splice_region_variant	Exon 8 of 14		NP_000109.1
ENG	NM_001278138.2	c.587C>A	p.Ala196Glu	missense_variant, splice_region_variant	Exon 8 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1133C>A	p.Ala378Glu	missense_variant, splice_region_variant	Exon 8 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1133C>A	p.Ala378Glu	missense_variant, splice_region_variant	Exon 8 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.587C>A	p.Ala196Glu	missense_variant, splice_region_variant	Exon 8 of 15	2		ENSP00000479015.1
ENG	ENST00000486329.1	n.101C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727170

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.2
DANN	Benign	0.79
DEOGEN2	Benign	0.31	T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L;.;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.99	N;.;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.29	B;.;.
Vest4		0.072
MutPred		0.31		Loss of ubiquitination at K373 (P = 0.0528);.;Loss of ubiquitination at K373 (P = 0.0528);
MVP		0.42
MPC		0.25
ClinPred		0.11	T
GERP RS		-0.021
Varity_R		0.096
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.16
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: chr9-130586584;