rs1060501411

Positions:

• chr9-127825325-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Moderate BP6_Moderate BS2

The NM_001114753.3(ENG):​c.722G>A​(p.Ser241Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.251

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 -6 ACMG points.

• PM1: In a region_of_interest OR1, C-terminal part (size 130) in uniprot entity EGLN_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001114753.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.21259317).
• BP6: Variant 9-127825325-C-T is Benign according to our data. Variant chr9-127825325-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 407116.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.722G>A	p.Ser241Asn	missense_variant	6/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.722G>A	p.Ser241Asn	missense_variant	6/14		NP_000109.1
ENG	NM_001278138.2	c.176G>A	p.Ser59Asn	missense_variant	6/15		NP_001265067.1
ENG	NM_001406715.1	c.722G>A	p.Ser241Asn	missense_variant	6/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.722G>A	p.Ser241Asn	missense_variant	6/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.722G>A	p.Ser241Asn	missense_variant	6/14	1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.176G>A	p.Ser59Asn	missense_variant	6/15	2		ENSP00000479015

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249874 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461082 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 726830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.36	T;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.84	N;.;N
REVEL	Benign	0.044
Sift	Benign	0.33	T;.;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0060	B;.;.
Vest4		0.18
MutPred		0.43		Loss of glycosylation at S241 (P = 0.057);.;Loss of glycosylation at S241 (P = 0.057);
MVP		0.39
MPC		0.22
ClinPred		0.050	T
GERP RS		0.58
Varity_R		0.17
gMVP		0.46

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: rs1060501411; hg19: chr9-130587604;