15-63126954-C-T

Variant names:

• chr15-63126954-C-T
• NM_032857.5:c.520C>T

Variant summary

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

The NM_032857.5(LACTB):​c.520C>T​(p.Leu174Phe) 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 1,461,338 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: 6.8e-7 (0 hom.)
• Consequence: LACTB NM_032857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LACTB	NM_032857.5	c.520C>T	p.Leu174Phe	missense_variant	Exon 3 of 6	ENST00000261893.9	NP_116246.2
LACTB	NM_171846.4	c.520C>T	p.Leu174Phe	missense_variant	Exon 3 of 5		NP_741982.1
LACTB	NM_001288585.2	c.520C>T	p.Leu174Phe	missense_variant	Exon 3 of 5		NP_001275514.1
LACTB	XM_047432128.1	c.520C>T	p.Leu174Phe	missense_variant	Exon 3 of 6		XP_047288084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LACTB	ENST00000261893.9	c.520C>T	p.Leu174Phe	missense_variant	Exon 3 of 6	1	NM_032857.5	ENSP00000261893.4
LACTB	ENST00000413507.3	c.520C>T	p.Leu174Phe	missense_variant	Exon 3 of 5	1		ENSP00000392956.2
LACTB	ENST00000557972.1	c.43C>T	p.Leu15Phe	missense_variant	Exon 2 of 3	2		ENSP00000454085.1
RPS27L	ENST00000559763.1	n.96-934G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461338 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727008

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

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

Oct 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.520C>T (p.L174F) alteration is located in exon 3 (coding exon 3) of the LACTB gene. This alteration results from a C to T substitution at nucleotide position 520, causing the leucine (L) at amino acid position 174 to be replaced by a phenylalanine (F). 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	0.54
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.045	D;D;D
Sift4G	Benign	0.072	T;T;D
Polyphen		0.96	D;.;.
Vest4		0.51
MutPred		0.64		Loss of MoRF binding (P = 0.1319);Loss of MoRF binding (P = 0.1319);.;
MVP		0.66
MPC		0.64
ClinPred		0.58	D
GERP RS		2.3
Varity_R		0.099
gMVP		0.74

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: chr15-63419153;