chr7-12369896-A-G

Variant names:

• chr7-12369896-A-G
• rs3823844
• NM_001135924.3:c.2410T>C

Variant summary

Our verdict is Benign. The variant received -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. 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 0.14 (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
• Publications: 13 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=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 rank	MANE	Protein	UniProt
VWDE	NM_001135924.3	c.2410T>C	p.Tyr804His	missense_variant	Exon 12 of 29	ENST00000275358.8	NP_001129396.1
VWDE	NM_001346972.2	c.2065T>C	p.Tyr689His	missense_variant	Exon 10 of 27		NP_001333901.1
VWDE	NM_001346973.2	c.1600T>C	p.Tyr534His	missense_variant	Exon 10 of 27		NP_001333902.1
VWDE	NR_144534.2	n.2559T>C		non_coding_transcript_exon_variant	Exon 12 of 30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWDE	ENST00000275358.8	c.2410T>C	p.Tyr804His	missense_variant	Exon 12 of 29	5	NM_001135924.3	ENSP00000275358.3
VWDE	ENST00000452576.6	n.2410T>C		non_coding_transcript_exon_variant	Exon 12 of 30	1		ENSP00000401687.2
VWDE	ENST00000521169.5	n.*788T>C		non_coding_transcript_exon_variant	Exon 9 of 26	5		ENSP00000428810.1
VWDE	ENST00000521169.5	n.*788T>C		3_prime_UTR_variant	Exon 9 of 26	5		ENSP00000428810.1

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

GnomAD2 exomes AF: 0.126 AC: 19738 AN: 156078 AF XY: 0.132

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 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

African (AFR) AF: 0.226 AC: 7135 AN: 31580

American (AMR) AF: 0.0643 AC: 2294 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0903 AC: 2272 AN: 25172

East Asian (EAS) AF: 0.222 AC: 7935 AN: 35738

South Asian (SAS) AF: 0.195 AC: 15433 AN: 79234

European-Finnish (FIN) AF: 0.113 AC: 5589 AN: 49274

Middle Eastern (MID) AF: 0.112 AC: 641 AN: 5698

European-Non Finnish (NFE) AF: 0.117 AC: 126025 AN: 1078856

Other (OTH) AF: 0.124 AC: 7219 AN: 57996

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

African (AFR) AF: 0.220 AC: 9115 AN: 41448

American (AMR) AF: 0.0821 AC: 1254 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0867 AC: 301 AN: 3470

East Asian (EAS) AF: 0.197 AC: 1008 AN: 5128

South Asian (SAS) AF: 0.206 AC: 995 AN: 4822

European-Finnish (FIN) AF: 0.119 AC: 1255 AN: 10590

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7558 AN: 67970

Other (OTH) AF: 0.113 AC: 238 AN: 2112

Alfa AF: 0.123 Hom.: 5743

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;.
PhyloP100		-1.5
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
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: rs3823844; hg19: chr7-12409522; COSMIC: COSV51733568;