rs35489000

chr5-10286356-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_138809.4(CMBL):c.464A>G(p.Tyr155Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000808 in 1,613,726 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (5 hom.)
• Consequence: CMBL NM_138809.4 missense, splice_region
• Scores: Splicing: ADA: 0.1579
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.00

Genes affected

CMBL (HGNC:25090): (carboxymethylenebutenolidase homolog) CMBL (EC 3.1.1.45) is a cysteine hydrolase of the dienelactone hydrolase family that is highly expressed in liver cytosol. CMBL preferentially cleaves cyclic esters, and it activates medoxomil-ester prodrugs in which the medoxomil moiety is linked to an oxygen atom (Ishizuka et al., 2010 [PubMed 20177059]).[supplied by OMIM, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024200082).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000435 (636/1461432) while in subpopulation AFR AF= 0.0172 (575/33468). AF 95% confidence interval is 0.016. There are 5 homozygotes in gnomad4_exome. There are 266 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CMBL	NM_138809.4	c.464A>G	p.Tyr155Cys	missense_variant, splice_region_variant	4/6	ENST00000296658.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CMBL	ENST00000296658.4	c.464A>G	p.Tyr155Cys	missense_variant, splice_region_variant	4/6	1	NM_138809.4	P1
CMBL	ENST00000506821.1	n.718A>G		non_coding_transcript_exon_variant	4/4	2
CMBL	ENST00000510532.5	n.532A>G		splice_region_variant, non_coding_transcript_exon_variant	4/5	3
CMBL	ENST00000511963.5	n.572A>G		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00439 AC: 668 AN: 152176 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.00143

GnomAD3 exomes AF: 0.000908 AC: 228 AN: 251098 Hom.: 2 AF XY: 0.000597 AC XY: 81 AN XY: 135702

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000435 AC: 636 AN: 1461432 Hom.: 5 Cov.: 30 AF XY: 0.000366 AC XY: 266 AN XY: 726984

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152294 Hom.: 4 Cov.: 31 AF XY: 0.00414 AC XY: 308 AN XY: 74470

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000757 Hom.: 1

Bravo AF: 0.00468

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.084	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.78
MPC		0.22
ClinPred		0.084	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35489000; hg19: chr5-10286468;