4-48988665-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_025087.3(CWH43):c.232A>G(p.Ile78Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,585,008 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (38 hom.)
• Consequence: CWH43 NM_025087.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.278

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067112744).
• BP6: Variant 4-48988665-A-G is Benign according to our data. Variant chr4-48988665-A-G is described in ClinVar as [Benign]. Clinvar id is 775963.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2110/152298) while in subpopulation AFR AF= 0.0439 (1824/41550). AF 95% confidence interval is 0.0422. There are 34 homozygotes in gnomad4. There are 1022 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CWH43	NM_025087.3	c.232A>G	p.Ile78Val	missense_variant	2/16	ENST00000226432.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CWH43	ENST00000226432.9	c.232A>G	p.Ile78Val	missense_variant	2/16	1	NM_025087.3	P1
CWH43	ENST00000513409.1	c.151A>G	p.Ile51Val	missense_variant	2/16	2
CWH43	ENST00000514053.6	c.232A>G	p.Ile78Val	missense_variant, NMD_transcript_variant	2/14	5

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2109 AN: 152182 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00438 AC: 988 AN: 225618 Hom.: 20 AF XY: 0.00350 AC XY: 426 AN XY: 121878

Gnomad AFR exome AF: 0.0456

Gnomad AMR exome AF: 0.00455

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.00207 AC: 2972 AN: 1432710 Hom.: 38 Cov.: 28 AF XY: 0.00188 AC XY: 1340 AN XY: 712338

Gnomad4 AFR exome AF: 0.0520

Gnomad4 AMR exome AF: 0.00527

Gnomad4 ASJ exome AF: 0.00317

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000160

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.000618

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.0139 AC: 2110 AN: 152298 Hom.: 34 Cov.: 32 AF XY: 0.0137 AC XY: 1022 AN XY: 74474

Gnomad4 AFR AF: 0.0439

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00291 Hom.: 15

Bravo AF: 0.0155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0436 AC: 192

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00466 AC: 566

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.1
Dann	Benign	0.26
DEOGEN2	Benign	0.0028	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.2	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.025
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.097
MVP		0.10
MPC		0.046
ClinPred		0.0037	T
GERP RS		1.4
Varity_R		0.022
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77901175; hg19: chr4-48990682;