7-12333467-G-A

Variant names:

• chr7-12333467-G-A
• rs547742882
• NM_001135924.3:c.4756C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001135924.3(VWDE):​c.4756C>T​(p.Gln1586*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VWDE NM_001135924.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9877
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21
• Publications: 0 publications found

Genes affected

VWDE (HGNC:21897): (von Willebrand factor D and EGF domains) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135924.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWDE	NM_001135924.3	MANE Select	c.4756C>T	p.Gln1586*	stop_gained splice_region	Exon 28 of 29	NP_001129396.1	Q8N2E2-1
	VWDE	NM_001346972.2		c.4411C>T	p.Gln1471*	stop_gained splice_region	Exon 26 of 27	NP_001333901.1
	VWDE	NM_001346973.2		c.3946C>T	p.Gln1316*	stop_gained splice_region	Exon 26 of 27	NP_001333902.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWDE	ENST00000275358.8	TSL:5 MANE Select	c.4756C>T	p.Gln1586*	stop_gained splice_region	Exon 28 of 29	ENSP00000275358.3	Q8N2E2-1
	VWDE	ENST00000452576.6	TSL:1	n.*1520C>T		splice_region non_coding_transcript_exon	Exon 29 of 30	ENSP00000401687.2	J3KQJ9
	VWDE	ENST00000452576.6	TSL:1	n.*1520C>T		3_prime_UTR	Exon 29 of 30	ENSP00000401687.2	J3KQJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382792 Hom.: 0 Cov.: 28 AF XY: 0.00000146 AC XY: 1 AN XY: 682724

African (AFR) AF: 0.00 AC: 0 AN: 31042

American (AMR) AF: 0.00 AC: 0 AN: 34750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24874

East Asian (EAS) AF: 0.00 AC: 0 AN: 35220

South Asian (SAS) AF: 0.00 AC: 0 AN: 77874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1066996

Other (OTH) AF: 0.00 AC: 0 AN: 57290

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	55
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		3.2
Vest4		0.064
GERP RS		2.8
Mutation Taster		=90/110	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.71		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs547742882; hg19: chr7-12373093;