NM_001135924.3:c.4756C>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135924.3(VWDE):​c.4756C>G​(p.Gln1586Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,534,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: VWDE NM_001135924.3 missense, splice_region
• Scores: Splicing: ADA: 0.0003762
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08597359).

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>G	p.Gln1586Glu	missense splice_region	Exon 28 of 29	NP_001129396.1	Q8N2E2-1
	VWDE	NM_001346972.2		c.4411C>G	p.Gln1471Glu	missense splice_region	Exon 26 of 27	NP_001333901.1
	VWDE	NM_001346973.2		c.3946C>G	p.Gln1316Glu	missense 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>G	p.Gln1586Glu	missense splice_region	Exon 28 of 29	ENSP00000275358.3	Q8N2E2-1
	VWDE	ENST00000452576.6	TSL:1	n.*1520C>G		splice_region non_coding_transcript_exon	Exon 29 of 30	ENSP00000401687.2	J3KQJ9
	VWDE	ENST00000452576.6	TSL:1	n.*1520C>G		3_prime_UTR	Exon 29 of 30	ENSP00000401687.2	J3KQJ9

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000197 AC: 3 AN: 151908 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000508

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 35 AN: 1382792 Hom.: 0 Cov.: 28 AF XY: 0.0000249 AC XY: 17 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: 0.0000309 AC: 33 AN: 1066996

Other (OTH) AF: 0.0000349 AC: 2 AN: 57290

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74406

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000165 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.085	N
PhyloP100		3.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.050
Sift	Benign	0.12	T
Sift4G	Uncertain	0.024	D
Polyphen		0.38	B
Vest4		0.26
MutPred		0.33		Loss of MoRF binding (P = 0.0142)
MVP		0.040
ClinPred		0.20	T
GERP RS		2.8
Varity_R		0.094
gMVP		0.50
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00038
dbscSNV1_RF	Benign	0.072
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		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; COSMIC: COSV99034403;