9-127825362-G-C

Variant names:

• chr9-127825362-G-C
• rs374628465
• NM_001114753.3:c.690-5C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001114753.3(ENG):​c.690-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ENG NM_001114753.3 splice_region, intron
• Scores: Splicing: ADA: 0.001125
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0950

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.690-5C>G		splice_region_variant, intron_variant	Intron 5 of 14	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.690-5C>G		splice_region_variant, intron_variant	Intron 5 of 13		NP_000109.1
ENG	NM_001278138.2	c.144-5C>G		splice_region_variant, intron_variant	Intron 5 of 14		NP_001265067.1
ENG	NM_001406715.1	c.690-5C>G		splice_region_variant, intron_variant	Intron 5 of 7		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.690-5C>G		splice_region_variant, intron_variant	Intron 5 of 14	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.690-5C>G		splice_region_variant, intron_variant	Intron 5 of 13	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.144-5C>G		splice_region_variant, intron_variant	Intron 5 of 14	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459560 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726138

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.4
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.060		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: rs374628465; hg19: chr9-130587641;