9-127824342-C-T

Variant names:

• chr9-127824342-C-T
• rs1800956
• NM_001114753.3:c.1096G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001114753.3(ENG):​c.1096G>A​(p.Asp366Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,870 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D366H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.23

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25109106).
• BP6: Variant 9-127824342-C-T is Benign according to our data. Variant chr9-127824342-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1356315.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1096G>A	p.Asp366Asn	missense_variant	Exon 8 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1096G>A	p.Asp366Asn	missense_variant	Exon 8 of 14		NP_000109.1
ENG	NM_001278138.2	c.550G>A	p.Asp184Asn	missense_variant	Exon 8 of 15		NP_001265067.1
ENG	NM_001406715.1	c.1096G>A	p.Asp366Asn	missense_variant	Exon 8 of 8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1096G>A	p.Asp366Asn	missense_variant	Exon 8 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1096G>A	p.Asp366Asn	missense_variant	Exon 8 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.550G>A	p.Asp184Asn	missense_variant	Exon 8 of 15	2		ENSP00000479015.1
ENG	ENST00000486329.1	n.64G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1

Feb 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hemorrhagic telangiectasia Benign:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Benign	0.22
Sift	Uncertain	0.027	D;.;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.22
MutPred		0.36		Loss of ubiquitination at K362 (P = 0.1179);.;Loss of ubiquitination at K362 (P = 0.1179);
MVP		0.82
MPC		0.75
ClinPred		0.88	D
GERP RS		3.6
Varity_R		0.18
gMVP		0.86

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: rs1800956; hg19: chr9-130586621;