15-63127564-G-A

Variant names:

• chr15-63127564-G-A
• rs201235539
• NM_032857.5:c.827G>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.827G>A​(p.Arg276Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: LACTB NM_032857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

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 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=0.040476203).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LACTB	NM_032857.5	c.827G>A	p.Arg276Gln	missense_variant	Exon 4 of 6	ENST00000261893.9	NP_116246.2
LACTB	NM_171846.4	c.827G>A	p.Arg276Gln	missense_variant	Exon 4 of 5		NP_741982.1
LACTB	NM_001288585.2	c.827G>A	p.Arg276Gln	missense_variant	Exon 4 of 5		NP_001275514.1
LACTB	XM_047432128.1	c.827G>A	p.Arg276Gln	missense_variant	Exon 4 of 6		XP_047288084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LACTB	ENST00000261893.9	c.827G>A	p.Arg276Gln	missense_variant	Exon 4 of 6	1	NM_032857.5	ENSP00000261893.4
LACTB	ENST00000413507.3	c.827G>A	p.Arg276Gln	missense_variant	Exon 4 of 5	1		ENSP00000392956.2
LACTB	ENST00000557972.1	c.350G>A	p.Arg117Gln	missense_variant	Exon 3 of 3	2		ENSP00000454085.1
RPS27L	ENST00000559763.1	n.96-1544C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000212 AC: 53 AN: 249798 Hom.: 0 AF XY: 0.000229 AC XY: 31 AN XY: 135512

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000245 AC: 358 AN: 1461264 Hom.: 0 Cov.: 31 AF XY: 0.000257 AC XY: 187 AN XY: 726928

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74426

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000274 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.827G>A (p.R276Q) alteration is located in exon 4 (coding exon 4) of the LACTB gene. This alteration results from a G to A substitution at nucleotide position 827, causing the arginine (R) at amino acid position 276 to be replaced by a glutamine (Q). 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	0.092
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0076	T;.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.39	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.20	T;T;D
Sift4G	Benign	0.21	T;T;T
Polyphen		0.020	B;.;.
Vest4		0.21
MVP		0.63
MPC		0.39
ClinPred		0.038	T
GERP RS		4.2
Varity_R		0.037
gMVP		0.23

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: rs201235539; hg19: chr15-63419763;