NM_022834.5:c.5T>A

Variant names:

• chr1-1435753-T-A
• NM_022834.5:c.5T>A

Variant summary

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

The NM_022834.5(VWA1):​c.5T>A​(p.Leu2His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000947 in 1,055,602 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.5e-7 (0 hom.)
• Consequence: VWA1 NM_022834.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.595
• Publications: 0 publications found

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]

LOC107985729 (HGNC:):

LINC01770 (HGNC:52560): (long intergenic non-protein coding RNA 1770)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022834.5. 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
	VWA1	NM_022834.5	MANE Select	c.5T>A	p.Leu2His	missense	Exon 1 of 3	NP_073745.2
	VWA1	NM_199121.3		c.5T>A	p.Leu2His	missense	Exon 1 of 3	NP_954572.2	Q6PCB0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA1	ENST00000476993.2	TSL:1 MANE Select	c.5T>A	p.Leu2His	missense	Exon 1 of 3	ENSP00000417185.1	Q6PCB0-1
	VWA1	ENST00000895635.1		c.5T>A	p.Leu2His	missense	Exon 1 of 3	ENSP00000565694.1
	VWA1	ENST00000895634.1		c.5T>A	p.Leu2His	missense	Exon 1 of 2	ENSP00000565693.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.47e-7 AC: 1 AN: 1055602 Hom.: 0 Cov.: 31 AF XY: 0.00000195 AC XY: 1 AN XY: 512232

African (AFR) AF: 0.00 AC: 0 AN: 20004

American (AMR) AF: 0.00 AC: 0 AN: 8136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12504

East Asian (EAS) AF: 0.00 AC: 0 AN: 14886

South Asian (SAS) AF: 0.00 AC: 0 AN: 39386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3332

European-Non Finnish (NFE) AF: 0.00000111 AC: 1 AN: 899658

Other (OTH) AF: 0.00 AC: 0 AN: 39000

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.21	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.59
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.37		Loss of catalytic residue at L2 (P = 8e-04)
MVP		0.80
MPC		0.28
ClinPred		0.97	D
GERP RS		2.8
PromoterAI		0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.33
gMVP		0.69
Mutation Taster		=77/23	polymorphism

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

hg19: chr1-1371133;