NM_015058.2:c.2972C>T

Variant names:

• chr13-41719735-G-A
• rs751179987
• NM_015058.2:c.2972C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_015058.2(VWA8):​c.2972C>T​(p.Pro991Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 1,603,384 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: VWA8 NM_015058.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.88
• Publications: 0 publications found

Genes affected

VWA8 (HGNC:29071): (von Willebrand factor A domain containing 8) Predicted to enable ATP binding activity. Located in mitochondrion and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

VWA8 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 97

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811
• BS2: High AC in GnomAdExome4 at 52 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015058.2. 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
	VWA8	NM_015058.2	MANE Select	c.2972C>T	p.Pro991Leu	missense	Exon 26 of 45	NP_055873.1	A3KMH1-1
	VWA8	NM_001009814.2		c.2972C>T	p.Pro991Leu	missense	Exon 26 of 26	NP_001009814.1	A3KMH1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VWA8	ENST00000379310.8	TSL:2 MANE Select	c.2972C>T	p.Pro991Leu	missense	Exon 26 of 45	ENSP00000368612.3	A3KMH1-1
	VWA8	ENST00000281496.6	TSL:1	c.2972C>T	p.Pro991Leu	missense	Exon 26 of 26	ENSP00000281496.6	A3KMH1-2
	VWA8	ENST00000938853.1		c.2972C>T	p.Pro991Leu	missense	Exon 26 of 45	ENSP00000608912.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151840 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000419 AC: 10 AN: 238686 AF XY: 0.0000466

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.0000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000358 AC: 52 AN: 1451544 Hom.: 1 Cov.: 31 AF XY: 0.0000416 AC XY: 30 AN XY: 721562

African (AFR) AF: 0.0000912 AC: 3 AN: 32894

American (AMR) AF: 0.00 AC: 0 AN: 42272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25772

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.000287 AC: 24 AN: 83596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1108510

Other (OTH) AF: 0.0000667 AC: 4 AN: 60008

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151840 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74152

African (AFR) AF: 0.0000242 AC: 1 AN: 41332

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67924

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-9.5	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.56		Gain of helix (P = 0.0325)
MVP		0.48
MPC		0.37
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.84
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs751179987; hg19: chr13-42293871; COSMIC: COSV99863408;