4-48998512-T-G

Variant names:

• chr4-48998512-T-G
• NM_025087.3:c.766T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_025087.3(CWH43):​c.766T>G​(p.Trp256Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CWH43 NM_025087.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CWH43	NM_025087.3	c.766T>G	p.Trp256Gly	missense_variant	Exon 6 of 16	ENST00000226432.9	NP_079363.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CWH43	ENST00000226432.9	c.766T>G	p.Trp256Gly	missense_variant	Exon 6 of 16	1	NM_025087.3	ENSP00000226432.4
CWH43	ENST00000513409.1	c.685T>G	p.Trp229Gly	missense_variant	Exon 6 of 16	2		ENSP00000422802.1
CWH43	ENST00000514053.6	n.717+3688T>G		intron_variant	Intron 5 of 13	5		ENSP00000425157.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.766T>G (p.W256G) alteration is located in exon 6 (coding exon 6) of the CWH43 gene. This alteration results from a T to G substitution at nucleotide position 766, causing the tryptophan (W) at amino acid position 256 to be replaced by a glycine (G). 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	0.089
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.22
Sift	Benign	0.26	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.68	P;.
Vest4		0.74
MutPred		0.63		Gain of relative solvent accessibility (P = 0.0215);.;
MVP		0.42
MPC		0.14
ClinPred		0.76	D
GERP RS		3.0
Varity_R		0.19
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: chr4-49000529;