rs35400405

Variant names:

• chr9-127854342-G-A
• rs35400405
• NM_001114753.3:c.14C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001114753.3(ENG):​c.14C>T​(p.Thr5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,593,366 control chromosomes in the GnomAD database, including 753 homozygotes. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T5T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.043 (259 hom., cov: 32)
  • Exomes 𝑓: 0.020 (494 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.282
• Publications: 17 publications found

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]

ENG Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_001114753.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018308163).
• BP6: Variant 9-127854342-G-A is Benign according to our data. Variant chr9-127854342-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114753.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	NM_001114753.3	MANE Select	c.14C>T	p.Thr5Met	missense	Exon 1 of 15	NP_001108225.1
	ENG	NM_000118.4		c.14C>T	p.Thr5Met	missense	Exon 1 of 14	NP_000109.1
	ENG	NM_001406715.1		c.14C>T	p.Thr5Met	missense	Exon 1 of 8	NP_001393644.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.14C>T	p.Thr5Met	missense	Exon 1 of 15	ENSP00000362299.4
	ENG	ENST00000344849.5	TSL:1	c.14C>T	p.Thr5Met	missense	Exon 1 of 14	ENSP00000341917.3
	ENG	ENST00000714047.1		c.14C>T	p.Thr5Met	missense	Exon 1 of 15	ENSP00000519338.1

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6610 AN: 152188 Hom.: 259 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0215 AC: 4471 AN: 207920 AF XY: 0.0192

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0217

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0204 AC: 29394 AN: 1441060 Hom.: 494 Cov.: 31 AF XY: 0.0197 AC XY: 14060 AN XY: 715048

African (AFR) AF: 0.115 AC: 3781 AN: 33008

American (AMR) AF: 0.0199 AC: 832 AN: 41764

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 571 AN: 25710

East Asian (EAS) AF: 0.00 AC: 0 AN: 38492

South Asian (SAS) AF: 0.00699 AC: 579 AN: 82852

European-Finnish (FIN) AF: 0.00559 AC: 288 AN: 51510

Middle Eastern (MID) AF: 0.0300 AC: 172 AN: 5732

European-Non Finnish (NFE) AF: 0.0198 AC: 21801 AN: 1102512

Other (OTH) AF: 0.0230 AC: 1370 AN: 59480

GnomAD4 genome AF: 0.0435 AC: 6621 AN: 152306 Hom.: 259 Cov.: 32 AF XY: 0.0410 AC XY: 3057 AN XY: 74482

African (AFR) AF: 0.104 AC: 4321 AN: 41558

American (AMR) AF: 0.0356 AC: 545 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4832

European-Finnish (FIN) AF: 0.00612 AC: 65 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1483 AN: 68024

Other (OTH) AF: 0.0436 AC: 92 AN: 2112

Alfa AF: 0.0268 Hom.: 135

Bravo AF: 0.0489

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.101 AC: 445

ESP6500EA AF: 0.0229 AC: 196

ExAC AF: 0.0216 AC: 2596

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Telangiectasia, hereditary hemorrhagic, type 1 (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.75
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.28
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.0030
Sift	Benign	0.15	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.019
MPC		0.22
ClinPred		0.00060	T
GERP RS		0.097
PromoterAI		0.092	Neutral
Varity_R		0.014
gMVP		0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35400405; hg19: chr9-130616621;