7-12351693-G-T

Position:

• chr7-12351693-G-T

Variant summary

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

The NM_001135924.3(VWDE):​c.3766C>A​(p.Gln1256Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 1,541,554 control chromosomes in the GnomAD database, including 158,731 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.55 (26034 hom., cov: 32)
  • Exomes 𝑓: 0.43 (132697 hom.)
• Consequence: VWDE NM_001135924.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.131

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]

VWDE (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3321682E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWDE	NM_001135924.3	c.3766C>A	p.Gln1256Lys	missense_variant	19/29	ENST00000275358.8	NP_001129396.1
VWDE	NM_001346972.2	c.3421C>A	p.Gln1141Lys	missense_variant	17/27		NP_001333901.1
VWDE	NM_001346973.2	c.2956C>A	p.Gln986Lys	missense_variant	17/27		NP_001333902.1
VWDE	NR_144534.2	n.4588C>A		non_coding_transcript_exon_variant	20/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8	c.3766C>A	p.Gln1256Lys	missense_variant	19/29	5	NM_001135924.3	ENSP00000275358.3

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83456 AN: 151900 Hom.: 25972 Cov.: 32

Gnomad AFR AF: 0.859

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.512

GnomAD3 exomes AF: 0.475 AC: 71523 AN: 150656 Hom.: 18343 AF XY: 0.465 AC XY: 37038 AN XY: 79586

Gnomad AFR exome AF: 0.877

Gnomad AMR exome AF: 0.579

Gnomad ASJ exome AF: 0.387

Gnomad EAS exome AF: 0.592

Gnomad SAS exome AF: 0.490

Gnomad FIN exome AF: 0.324

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.449

GnomAD4 exome AF: 0.427 AC: 594024 AN: 1389536 Hom.: 132697 Cov.: 32 AF XY: 0.428 AC XY: 292984 AN XY: 685132

Gnomad4 AFR exome AF: 0.878

Gnomad4 AMR exome AF: 0.576

Gnomad4 ASJ exome AF: 0.377

Gnomad4 EAS exome AF: 0.591

Gnomad4 SAS exome AF: 0.494

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.448

GnomAD4 genome AF: 0.550 AC: 83577 AN: 152018 Hom.: 26034 Cov.: 32 AF XY: 0.546 AC XY: 40528 AN XY: 74288

Gnomad4 AFR AF: 0.859

Gnomad4 AMR AF: 0.539

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.585

Gnomad4 SAS AF: 0.498

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.513

Alfa AF: 0.440 Hom.: 20965

Bravo AF: 0.581

TwinsUK AF: 0.400 AC: 1484

ALSPAC AF: 0.409 AC: 1578

ExAC AF: 0.462 AC: 10918

Asia WGS AF: 0.573 AC: 1992 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.36
DANN	Benign	0.17
DEOGEN2	Benign	0.018	T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.15	T;T;T
MetaRNN	Benign	0.0000013	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.030	N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.29	N;.;.
REVEL	Benign	0.11
Sift	Benign	0.76	T;.;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.053
ClinPred		0.0032	T
GERP RS		-1.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.6
Varity_R		0.055
gMVP		0.50

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: rs6967385; hg19: chr7-12391319; COSMIC: COSV51719881;