rs537154767

Variant names:

• chr9-127825273-G-A
• rs537154767
• NM_001114753.3:c.774C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-127825273-G-A
• chr9-127825273-G-C
• chr9-127825273-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001114753.3(ENG):​c.774C>T​(p.Tyr258Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ENG NM_001114753.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.449
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-127825273-G-A is Benign according to our data. Variant chr9-127825273-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 414313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.449 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	NM_001114753.3	MANE Select	c.774C>T	p.Tyr258Tyr	synonymous	Exon 6 of 15	NP_001108225.1
	ENG	NM_000118.4		c.774C>T	p.Tyr258Tyr	synonymous	Exon 6 of 14	NP_000109.1
	ENG	NM_001278138.2		c.228C>T	p.Tyr76Tyr	synonymous	Exon 6 of 15	NP_001265067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENG	ENST00000373203.9	TSL:1 MANE Select	c.774C>T	p.Tyr258Tyr	synonymous	Exon 6 of 15	ENSP00000362299.4
	ENG	ENST00000344849.5	TSL:1	c.774C>T	p.Tyr258Tyr	synonymous	Exon 6 of 14	ENSP00000341917.3
	ENG	ENST00000714078.1		c.-31C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	ENSP00000519369.1

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150796 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250768 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461678 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112002

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 150914 Hom.: 0 Cov.: 27 AF XY: 0.0000272 AC XY: 2 AN XY: 73602

African (AFR) AF: 0.0000973 AC: 4 AN: 41104

American (AMR) AF: 0.0000665 AC: 1 AN: 15042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67718

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hereditary hemorrhagic telangiectasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		-0.45

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: rs537154767; hg19: chr9-130587552;