rs3823844

Positions:

• chr7-12369896-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001135924.3(VWDE):​c.2410T>C​(p.Tyr804His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,551,264 control chromosomes in the GnomAD database, including 13,693 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1862 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11831 hom.)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014323086).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWDE	NM_001135924.3	c.2410T>C	p.Tyr804His	missense_variant	12/29	ENST00000275358.8	NP_001129396.1
VWDE	NM_001346972.2	c.2065T>C	p.Tyr689His	missense_variant	10/27		NP_001333901.1
VWDE	NM_001346973.2	c.1600T>C	p.Tyr534His	missense_variant	10/27		NP_001333902.1
VWDE	NR_144534.2	n.2559T>C		non_coding_transcript_exon_variant	12/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8	c.2410T>C	p.Tyr804His	missense_variant	12/29	5	NM_001135924.3	ENSP00000275358	P1
VWDE	ENST00000452576.6	c.2410T>C	p.Tyr804His	missense_variant, NMD_transcript_variant	12/30	1		ENSP00000401687
VWDE	ENST00000521169.5	c.*788T>C		3_prime_UTR_variant, NMD_transcript_variant	9/26	5		ENSP00000428810

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21849 AN: 151896 Hom.: 1862 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.126 AC: 19738 AN: 156078 Hom.: 1482 AF XY: 0.132 AC XY: 10901 AN XY: 82708

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0586

Gnomad ASJ exome AF: 0.0949

Gnomad EAS exome AF: 0.198

Gnomad SAS exome AF: 0.193

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.0993

GnomAD4 exome AF: 0.125 AC: 174543 AN: 1399250 Hom.: 11831 Cov.: 32 AF XY: 0.126 AC XY: 87272 AN XY: 690134

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.0643

Gnomad4 ASJ exome AF: 0.0903

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.195

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.144 AC: 21870 AN: 152014 Hom.: 1862 Cov.: 32 AF XY: 0.145 AC XY: 10759 AN XY: 74308

Gnomad4 AFR AF: 0.220

Gnomad4 AMR AF: 0.0821

Gnomad4 ASJ AF: 0.0867

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.113

Alfa AF: 0.120 Hom.: 2879

Bravo AF: 0.144

TwinsUK AF: 0.111 AC: 411

ALSPAC AF: 0.120 AC: 464

ESP6500AA AF: 0.231 AC: 320

ESP6500EA AF: 0.115 AC: 366

ExAC AF: 0.141 AC: 3518

Asia WGS AF: 0.181 AC: 628 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0060
DANN	Benign	0.22
DEOGEN2	Benign	0.016	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.070	N;.
REVEL	Benign	0.11
Sift	Benign	0.55	T;.
Sift4G	Benign	0.51	T;T
Polyphen		0.0	B;.
Vest4		0.023
ClinPred		0.0081	T
GERP RS		-9.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs3823844; hg19: chr7-12409522; COSMIC: COSV51733568;