rs368533266

chr9-127818828-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001114753.3(ENG):c.1316A>C(p.Lys439Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000856 in 1,612,018 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K439N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:2
• 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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, 7 uncertain in NM_001114753.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.041983545).
• BP6: Variant 9-127818828-T-G is Benign according to our data. Variant chr9-127818828-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 365088.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000897 (131/1459986) while in subpopulation MID AF= 0.00174 (10/5734). AF 95% confidence interval is 0.000946. There are 0 homozygotes in gnomad4_exome. There are 79 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1316A>C	p.Lys439Thr	missense_variant	11/15	ENST00000373203.9
LOC102723566	NR_136302.1	n.1568+117T>G		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1316A>C	p.Lys439Thr	missense_variant	11/14
ENG	NM_001278138.2	c.770A>C	p.Lys257Thr	missense_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1316A>C	p.Lys439Thr	missense_variant	11/15	1	NM_001114753.3	P2
	ENST00000439298.5	n.1568+117T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251416 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135888

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000897 AC: 131 AN: 1459986 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 726294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74258

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000313 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Uncertain:1 Benign:1

Likely benign, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	The NM_001114753.3: c.1316A>C variant in ENG is a missense variant predicted to cause substitution of lysine by threonine at amino acid 439 (p.Lys439Thr). The filtering allele frequency (the lower threshold of the 95% CI of 15/10368) of the c.1316A>C variant in ENG is 0.0008918 for Ashkenazi Jewish chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.0008-0.002) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.041, which is below the threshold of less than or equal to 0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). Additionally, functional assays showed the variant protein localized to the cell surface and had normal BMP9 response indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1_Supporting, BP4, BS3_Supporting (specification version 1.0.0; 1/4/2024). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 14, 2017

The c.1316A>C; p.Lys439Thr variant (rs368533266) was reported in a patient that carried a deletion in exon 6 of the ENG gene (Mallet, 2015). Functional studies by Mallet (2015) also showed that the p.Lys439Thr is properly targeted to the cell surface and stimulates ALK1 signaling in response to BMP9, features that are otherwise reduced in defective ENG polypeptides. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.15 percent in the Ashkenazi Jewish population (identified on 15 out of 9,850 chromosomes), and is reported to the ClinVar database (Variation ID: 365088). The lysine at position 439 is moderately conserved considering 12 species (Alamut v2.9.0) and computational analyses of the p.Lys439Thr variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on these observations, the p.Lys439Thr variant is likely to be benign. -

Hereditary hemorrhagic telangiectasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	8.9
Dann	Benign	0.93
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.041
Sift	Benign	0.085	T;.;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.023	B;.;.
Vest4		0.21
MVP		0.26
MPC		0.27
ClinPred		0.0049	T
GERP RS		0.63
Varity_R		0.23
gMVP		0.77

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: rs368533266; hg19: chr9-130581107;