16-22100460-A-G

Variant names:

• chr16-22100460-A-G
• rs1222836085
• NM_173615.5:c.395A>G

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.395A>G​(p.Gln132Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,410 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q132E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: VWA3A NM_173615.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• 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=0.08930829).

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.395A>G	p.Gln132Arg	missense	Exon 5 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.395A>G	p.Gln132Arg	missense	Exon 5 of 34	ENSP00000374049.5	A6NCI4-1
	VWA3A	ENST00000568328.5	TSL:1	c.395A>G	p.Gln132Arg	missense	Exon 5 of 23	ENSP00000457770.1	H3BUS3
	VWA3A	ENST00000877573.1		c.395A>G	p.Gln132Arg	missense	Exon 5 of 33	ENSP00000547632.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399410 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690210

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078976

Other (OTH) AF: 0.00 AC: 0 AN: 58002

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.9
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.072
Sift	Benign	0.39	T
Sift4G	Benign	0.21	T
Polyphen		0.0050	B
Vest4		0.13
MutPred		0.52		Gain of MoRF binding (P = 0.0278)
MVP		0.061
MPC		0.046
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.11
gMVP		0.070

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1222836085; hg19: chr16-22111781;