dbSNP rs764506256: CWH43:p.Pro59His (chr4-48988609-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_025087.3(CWH43):c.176C>A(p.Pro59His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P59R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CWH43
NM_025087.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.25

Publications

0 publications found

Variant links:

Genes affected

CWH43 (HGNC:26133): (cell wall biogenesis 43 C-terminal homolog) Predicted to be involved in GPI anchor biosynthetic process. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

CWH43 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025087.3. 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
	CWH43	NM_025087.3	MANE Select	c.176C>A	p.Pro59His	missense	Exon 2 of 16	NP_079363.2	Q9H720
	CWH43	NM_001286791.2		c.95C>A	p.Pro32His	missense	Exon 2 of 16	NP_001273720.1	E7EQL2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CWH43	ENST00000226432.9	TSL:1 MANE Select	c.176C>A	p.Pro59His	missense	Exon 2 of 16	ENSP00000226432.4	Q9H720
CWH43	ENST00000856986.1		c.176C>A	p.Pro59His	missense	Exon 2 of 16	ENSP00000527045.1
CWH43	ENST00000856987.1		c.176C>A	p.Pro59His	missense	Exon 2 of 16	ENSP00000527046.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250944

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461016

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111420

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.75

M_CAP

Benign

0.015

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.7

PhyloP100

3.2

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.8

REVEL

Benign

0.22

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.75

MutPred

0.53

Loss of catalytic residue at P59 (P = 0.0389)

MVP

0.61

MPC

0.30

ClinPred

0.98

GERP RS

5.0

Varity_R

0.34

gMVP

0.43

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over