rs41355248

Positions:

• chr9-127829666-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001114753.3(ENG):​c.360+21C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,613,686 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (71 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (73 hom.)
• Consequence: ENG NM_001114753.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.437

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-127829666-G-A is Benign according to our data. Variant chr9-127829666-G-A is described in ClinVar as [Benign]. Clinvar id is 255145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.360+21C>T		intron_variant		ENST00000373203.9
ENG	NM_000118.4	c.360+21C>T		intron_variant
ENG	NM_001278138.2	c.-187+21C>T		intron_variant
ENG	NM_001406715.1	c.360+21C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.360+21C>T		intron_variant		1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.360+21C>T		intron_variant		1		A2
ENG	ENST00000480266.6	c.-187+21C>T		intron_variant		2
ENG	ENST00000462196.1	n.118+21C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2620 AN: 152138 Hom.: 71 Cov.: 31

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00475 AC: 1188 AN: 250204 Hom.: 30 AF XY: 0.00353 AC XY: 478 AN XY: 135314

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.00507

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00191 AC: 2792 AN: 1461430 Hom.: 73 Cov.: 31 AF XY: 0.00164 AC XY: 1195 AN XY: 727008

Gnomad4 AFR exome AF: 0.0595

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.00467

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00414

GnomAD4 genome AF: 0.0173 AC: 2630 AN: 152256 Hom.: 71 Cov.: 31 AF XY: 0.0170 AC XY: 1265 AN XY: 74440

Gnomad4 AFR AF: 0.0590

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0108 Hom.: 12

Bravo AF: 0.0192

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 15, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.0
DANN	Benign	0.69

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: rs41355248; hg19: chr9-130591945;