chr4-48998518-C-T

Variant names:

• chr4-48998518-C-T
• rs762343467
• NM_025087.3:c.772C>T

Variant summary

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

The NM_025087.3(CWH43):​c.772C>T​(p.Arg258Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: CWH43 NM_025087.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.135
• Publications: 4 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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.772C>T	p.Arg258Cys	missense	Exon 6 of 16	NP_079363.2	Q9H720
	CWH43	NM_001286791.2		c.691C>T	p.Arg231Cys	missense	Exon 6 of 16	NP_001273720.1	E7EQL2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CWH43	ENST00000226432.9	TSL:1 MANE Select	c.772C>T	p.Arg258Cys	missense	Exon 6 of 16	ENSP00000226432.4	Q9H720
	CWH43	ENST00000856986.1		c.772C>T	p.Arg258Cys	missense	Exon 6 of 16	ENSP00000527045.1
	CWH43	ENST00000856987.1		c.772C>T	p.Arg258Cys	missense	Exon 6 of 16	ENSP00000527046.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251452 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461592 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 727086

African (AFR) AF: 0.0000897 AC: 3 AN: 33458

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111776

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74274

African (AFR) AF: 0.0000725 AC: 3 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

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

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.099
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.61
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.14
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.068
Sift	Benign	0.18	T
Sift4G	Benign	0.21	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.53		Loss of methylation at R258 (P = 0.0248)
MVP		0.21
MPC		0.067
ClinPred		0.044	T
GERP RS		2.4
Varity_R		0.051
gMVP		0.72
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762343467; hg19: chr4-49000535; COSMIC: COSV56939862;