1-1435753-T-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA1	NM_022834.5	c.5T>A	p.Leu2His	missense_variant	Exon 1 of 3	ENST00000476993.2	NP_073745.2
VWA1	NM_199121.3	c.5T>A	p.Leu2His	missense_variant	Exon 1 of 3		NP_954572.2
LOC107985729	XM_017003066.2	c.*603T>A		downstream_gene_variant			XP_016858555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWA1	ENST00000476993.2	c.5T>A	p.Leu2His	missense_variant	Exon 1 of 3	1	NM_022834.5	ENSP00000417185.1
VWA1	ENST00000471398.1	c.5T>A	p.Leu2His	missense_variant	Exon 1 of 2	3		ENSP00000464343.1
VWA1	ENST00000338660.5	c.5T>A	p.Leu2His	missense_variant	Exon 1 of 3	2		ENSP00000423404.1
VWA1	ENST00000495558.1	c.-33+607T>A		intron_variant	Intron 1 of 1	2		ENSP00000463643.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5T>A (p.L2H) alteration is located in exon 1 (coding exon 1) of the VWA1 gene. This alteration results from a T to A substitution at nucleotide position 5, causing the leucine (L) at amino acid position 2 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.50	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.97	L;L;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.0	D;N;.
REVEL	Benign	0.19
Sift	Pathogenic	0.0	.;D;.
Sift4G	Uncertain	0.0020	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.37
MutPred		0.37		Loss of catalytic residue at L2 (P = 8e-04);Loss of catalytic residue at L2 (P = 8e-04);Loss of catalytic residue at L2 (P = 8e-04);
MVP		0.80
MPC		0.28
ClinPred		0.97	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.33
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1371133;