15-63141420-T-C

Variant names:

• chr15-63141420-T-C
• NM_032857.5:c.1259T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032857.5(LACTB):​c.1259T>C​(p.Val420Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LACTB NM_032857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.26

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]

RPS27L (HGNC:18476): (ribosomal protein S27 like) This gene encodes a protein sharing 96% amino acid similarity with ribosomal protein S27, which suggests the encoded protein may be a component of the 40S ribosomal subunit. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10618836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LACTB	NM_032857.5	c.1259T>C	p.Val420Ala	missense_variant	Exon 6 of 6	ENST00000261893.9	NP_116246.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LACTB	ENST00000261893.9	c.1259T>C	p.Val420Ala	missense_variant	Exon 6 of 6	1	NM_032857.5	ENSP00000261893.4
RPS27L	ENST00000559763.1	n.95+14201A>G		intron_variant	Intron 1 of 1	3
LACTB	ENST00000559782.1	n.*74T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1259T>C (p.V420A) alteration is located in exon 6 (coding exon 6) of the LACTB gene. This alteration results from a T to C substitution at nucleotide position 1259, causing the valine (V) at amino acid position 420 to be replaced by an alanine (A). 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	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.063
Sift	Benign	0.57	T
Sift4G	Benign	0.93	T
Polyphen		0.0010	B
Vest4		0.076
MutPred		0.54		Loss of sheet (P = 0.0104);
MVP		0.42
MPC		0.41
ClinPred		0.16	T
GERP RS		4.4
Varity_R		0.039
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-63433619;