NM_001039500.3:c.47C>G

Variant names:

• chr1-20310648-C-G
• rs1322056739
• NM_001039500.3:c.47C>G

Variant summary

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

The NM_001039500.3(VWA5B1):​c.47C>G​(p.Thr16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000709 in 1,550,590 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: VWA5B1 NM_001039500.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• Publications: 0 publications found

Genes affected

VWA5B1 (HGNC:26538): (von Willebrand factor A domain containing 5B1) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000226664 (HGNC:41146):

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=0.14024943).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039500.3. 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
	VWA5B1	NM_001039500.3	MANE Select	c.47C>G	p.Thr16Ser	missense	Exon 2 of 22	NP_001034589.2	Q5TIE3-2
	VWA5B1	NM_001377531.1		c.-213C>G		5_prime_UTR	Exon 2 of 22	NP_001364460.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA5B1	ENST00000289815.13	TSL:5 MANE Select	c.47C>G	p.Thr16Ser	missense	Exon 2 of 22	ENSP00000289815.9	Q5TIE3-2
	VWA5B1	ENST00000919186.1		c.47C>G	p.Thr16Ser	missense	Exon 2 of 22	ENSP00000589245.1
	VWA5B1	ENST00000375079.6	TSL:5	c.47C>G	p.Thr16Ser	missense	Exon 2 of 22	ENSP00000364220.1	Q5TIE3-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000128 AC: 2 AN: 155830 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000186

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000715 AC: 10 AN: 1398474 Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5 AN XY: 689786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31570

American (AMR) AF: 0.00 AC: 0 AN: 35468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.0000842 AC: 3 AN: 35610

South Asian (SAS) AF: 0.00 AC: 0 AN: 79090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000649 AC: 7 AN: 1078592

Other (OTH) AF: 0.00 AC: 0 AN: 57982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000028857), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.18
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.00078	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.067
Sift	Benign	0.26	T
Sift4G	Benign	0.41	T
Polyphen		0.32	B
Vest4		0.12
MutPred		0.30		Gain of sheet (P = 0.0221)
MVP		0.030
ClinPred		0.16	T
GERP RS		4.5
Varity_R		0.088
gMVP		0.10
Mutation Taster		=90/10	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

dbSNP: rs1322056739; hg19: chr1-20637141;