16-22115423-A-C

Variant names:

• chr16-22115423-A-C
• rs770796122
• NM_173615.5:c.766A>C

Variant summary

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

The NM_173615.5(VWA3A):​c.766A>C​(p.Ile256Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I256F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: VWA3A NM_173615.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397
• Publications: 0 publications found

Genes affected

VWA3A (HGNC:27088): (von Willebrand factor A domain containing 3A) Predicted to be located in 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=0.114967525).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173615.5. 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
	VWA3A	NM_173615.5	MANE Select	c.766A>C	p.Ile256Leu	missense	Exon 9 of 34	NP_775886.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA3A	ENST00000389398.10	TSL:5 MANE Select	c.766A>C	p.Ile256Leu	missense	Exon 9 of 34	ENSP00000374049.5	A6NCI4-1
	VWA3A	ENST00000568328.5	TSL:1	c.766A>C	p.Ile256Leu	missense	Exon 9 of 23	ENSP00000457770.1	H3BUS3
	VWA3A	ENST00000877573.1		c.766A>C	p.Ile256Leu	missense	Exon 9 of 33	ENSP00000547632.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.3
DANN	Benign	0.73
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.40
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.093
Sift	Benign	0.063	T
Sift4G	Uncertain	0.058	T
Polyphen		0.0080	B
Vest4		0.11
MutPred		0.67		Gain of ubiquitination at K254 (P = 0.1557)
MVP		0.030
MPC		0.046
ClinPred		0.12	T
GERP RS		-11
Varity_R		0.11
gMVP		0.39

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: rs770796122; hg19: chr16-22126744;