15-63121914-C-A

Position:

• chr15-63121914-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032857.5(LACTB):​c.43C>A​(p.Pro15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000236 in 1,269,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: LACTB NM_032857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0380

Genes affected

LACTB (HGNC:16468): (lactamase beta) This gene encodes a mitochondrially-localized protein that has sequence similarity to prokaryotic beta-lactamases. Many of the residues responsible for beta-lactamase activity are not conserved in this protein, suggesting it may have a different enzymatic function. Increased expression of the related mouse gene was found to be associated with obesity. Alternative splicing results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042765856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LACTB	NM_032857.5	c.43C>A	p.Pro15Thr	missense_variant	1/6	ENST00000261893.9	NP_116246.2
LACTB	NM_171846.4	c.43C>A	p.Pro15Thr	missense_variant	1/5		NP_741982.1
LACTB	NM_001288585.2	c.43C>A	p.Pro15Thr	missense_variant	1/5		NP_001275514.1
LACTB	XM_047432128.1	c.43C>A	p.Pro15Thr	missense_variant	1/6		XP_047288084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LACTB	ENST00000261893.9	c.43C>A	p.Pro15Thr	missense_variant	1/6	1	NM_032857.5	ENSP00000261893.4
LACTB	ENST00000413507.3	c.43C>A	p.Pro15Thr	missense_variant	1/5	1		ENSP00000392956.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000236 AC: 3 AN: 1269946 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 625188

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2024

The c.43C>A (p.P15T) alteration is located in exon 1 (coding exon 1) of the LACTB gene. This alteration results from a C to A substitution at nucleotide position 43, causing the proline (P) at amino acid position 15 to be replaced by a threonine (T). 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	0.066
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.63
DANN	Benign	0.82
DEOGEN2	Benign	0.0057	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.48	N;N
REVEL	Benign	0.023
Sift	Benign	1.0	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0	B;.
Vest4		0.061
MutPred		0.17		Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);
MVP		0.14
MPC		0.37
ClinPred		0.033	T
GERP RS		0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.092
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs1234763364; hg19: chr15-63414113;