rs375025857

Variant names:

• chr9-127825845-G-A
• rs375025857
• NM_001114753.3:c.539C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001114753.3(ENG):​c.539C>T​(p.Ser180Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,442,552 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: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.500

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07475731).
• BP6: Variant 9-127825845-G-A is Benign according to our data. Variant chr9-127825845-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 528054.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.539C>T	p.Ser180Phe	missense_variant	Exon 5 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.539C>T	p.Ser180Phe	missense_variant	Exon 5 of 14		NP_000109.1
ENG	NM_001406715.1	c.539C>T	p.Ser180Phe	missense_variant	Exon 5 of 8		NP_001393644.1
ENG	NM_001278138.2	c.-8C>T		5_prime_UTR_variant	Exon 5 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.539C>T	p.Ser180Phe	missense_variant	Exon 5 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.539C>T	p.Ser180Phe	missense_variant	Exon 5 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-8C>T		5_prime_UTR_variant	Exon 5 of 15	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.439C>T		non_coding_transcript_exon_variant	Exon 4 of 4	3		ENSP00000519251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000142 AC: 3 AN: 211824 Hom.: 0 AF XY: 0.0000173 AC XY: 2 AN XY: 115482

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: 0.0000327

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 21 AN: 1442552 Hom.: 0 Cov.: 34 AF XY: 0.0000168 AC XY: 12 AN XY: 715998

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: 0.0000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Benign:1

Feb 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.70
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.017
Sift	Benign	0.35	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0010	B;.
Vest4		0.19
MVP		0.27
MPC		0.23
ClinPred		0.030	T
GERP RS		-0.77
Varity_R		0.17
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs375025857; hg19: chr9-130588124;