1-1436942-C-A

Variant names:

• chr1-1436942-C-A
• rs764874190
• NM_022834.5:c.89C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022834.5(VWA1):​c.89C>A​(p.Ala30Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A30V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VWA1 NM_022834.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.148

Genes affected

VWA1 (HGNC:30910): (von Willebrand factor A domain containing 1) VWA1 belongs to the von Willebrand factor (VWF; MIM 613160) A (VWFA) domain superfamily of extracellular matrix proteins and appears to play a role in cartilage structure and function (Fitzgerald et al., 2002 [PubMed 12062410]).[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065956384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA1	NM_022834.5	c.89C>A	p.Ala30Asp	missense_variant	Exon 2 of 3	ENST00000476993.2	NP_073745.2
VWA1	NM_199121.3	c.74-380C>A		intron_variant	Intron 1 of 2		NP_954572.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWA1	ENST00000476993.2	c.89C>A	p.Ala30Asp	missense_variant	Exon 2 of 3	1	NM_022834.5	ENSP00000417185.1
VWA1	ENST00000471398.1	c.209C>A	p.Ala70Asp	missense_variant	Exon 2 of 2	3		ENSP00000464343.1
VWA1	ENST00000495558	c.-17C>A		5_prime_UTR_variant	Exon 2 of 2	2		ENSP00000463643.1
VWA1	ENST00000338660.5	c.74-380C>A		intron_variant	Intron 1 of 2	2		ENSP00000423404.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447458 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.57	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.73	N;.
REVEL	Benign	0.020
Sift	Benign	0.52	T;.
Sift4G	Benign	0.31	T;T
Polyphen		0.0030	B;.
Vest4		0.28
MutPred		0.19		Loss of glycosylation at S29 (P = 0.0725);.;
MVP		0.34
MPC		0.044
ClinPred		0.094	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.095
gMVP		0.37

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: rs764874190; hg19: chr1-1372322;