7-12351693-G-T

Variant names:

• chr7-12351693-G-T
• rs6967385
• NM_001135924.3:c.3766C>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 0.55 (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
• Publications: 29 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: Benign. The variant received -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.

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.3766C>A	p.Gln1256Lys	missense	Exon 19 of 29	NP_001129396.1	Q8N2E2-1
	VWDE	NM_001346972.2		c.3421C>A	p.Gln1141Lys	missense	Exon 17 of 27	NP_001333901.1
	VWDE	NM_001346973.2		c.2956C>A	p.Gln986Lys	missense	Exon 17 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.3766C>A	p.Gln1256Lys	missense	Exon 19 of 29	ENSP00000275358.3	Q8N2E2-1
	VWDE	ENST00000452576.6	TSL:1	n.*530C>A		non_coding_transcript_exon	Exon 20 of 30	ENSP00000401687.2	J3KQJ9
	VWDE	ENST00000452576.6	TSL:1	n.*530C>A		3_prime_UTR	Exon 20 of 30	ENSP00000401687.2	J3KQJ9

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

GnomAD2 exomes AF: 0.475 AC: 71523 AN: 150656 AF XY: 0.465

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 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

African (AFR) AF: 0.878 AC: 27339 AN: 31128

American (AMR) AF: 0.576 AC: 19983 AN: 34674

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 9388 AN: 24898

East Asian (EAS) AF: 0.591 AC: 20999 AN: 35516

South Asian (SAS) AF: 0.494 AC: 38238 AN: 77328

European-Finnish (FIN) AF: 0.329 AC: 16100 AN: 48886

Middle Eastern (MID) AF: 0.514 AC: 2716 AN: 5282

European-Non Finnish (NFE) AF: 0.403 AC: 433437 AN: 1074230

Other (OTH) AF: 0.448 AC: 25824 AN: 57594

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

African (AFR) AF: 0.859 AC: 35670 AN: 41514

American (AMR) AF: 0.539 AC: 8209 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1343 AN: 3470

East Asian (EAS) AF: 0.585 AC: 3016 AN: 5156

South Asian (SAS) AF: 0.498 AC: 2400 AN: 4818

European-Finnish (FIN) AF: 0.329 AC: 3467 AN: 10550

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27759 AN: 67952

Other (OTH) AF: 0.513 AC: 1082 AN: 2108

Alfa AF: 0.441 Hom.: 44404

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 v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.030	N
PhyloP100		-0.13
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.11
Sift	Benign	0.76	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.053
ClinPred		0.0032	T
GERP RS		-1.1
PromoterAI		-0.0030	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.6
Varity_R		0.055
gMVP		0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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