15-63121878-C-T

Position:

• chr15-63121878-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000261893.9(LACTB):​c.7C>T​(p.Arg3Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 1,241,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: LACTB ENST00000261893.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LACTB	NM_032857.5	c.7C>T	p.Arg3Trp	missense_variant	1/6	ENST00000261893.9	NP_116246.2
LACTB	NM_171846.4	c.7C>T	p.Arg3Trp	missense_variant	1/5		NP_741982.1
LACTB	NM_001288585.2	c.7C>T	p.Arg3Trp	missense_variant	1/5		NP_001275514.1
LACTB	XM_047432128.1	c.7C>T	p.Arg3Trp	missense_variant	1/6		XP_047288084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LACTB	ENST00000261893.9	c.7C>T	p.Arg3Trp	missense_variant	1/6	1	NM_032857.5	ENSP00000261893.4
LACTB	ENST00000413507.3	c.7C>T	p.Arg3Trp	missense_variant	1/5	1		ENSP00000392956.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000242 AC: 3 AN: 1241816 Hom.: 0 Cov.: 35 AF XY: 0.00000164 AC XY: 1 AN XY: 608090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000554

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Feb 13, 2024

The c.7C>T (p.R3W) alteration is located in exon 1 (coding exon 1) of the LACTB gene. This alteration results from a C to T substitution at nucleotide position 7, causing the arginine (R) at amino acid position 3 to be replaced by a tryptophan (W). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	0.078
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.62	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.49
MutPred		0.44		Loss of disorder (P = 0);Loss of disorder (P = 0);
MVP		0.78
MPC		1.0
ClinPred		0.77	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.35
gMVP		0.61

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: rs771795019; hg19: chr15-63414077;