chr15-63127641-A-G

Variant names:

• chr15-63127641-A-G
• rs142381405
• NM_032857.5:c.904A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032857.5(LACTB):​c.904A>G​(p.Ile302Val) variant causes a missense change. The variant allele was found at a frequency of 0.000192 in 1,608,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I302F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: LACTB NM_032857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044537842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LACTB	NM_032857.5	c.904A>G	p.Ile302Val	missense_variant	Exon 4 of 6	ENST00000261893.9	NP_116246.2
LACTB	NM_171846.4	c.904A>G	p.Ile302Val	missense_variant	Exon 4 of 5		NP_741982.1
LACTB	NM_001288585.2	c.904A>G	p.Ile302Val	missense_variant	Exon 4 of 5		NP_001275514.1
LACTB	XM_047432128.1	c.904A>G	p.Ile302Val	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.904A>G	p.Ile302Val	missense_variant	Exon 4 of 6	1	NM_032857.5	ENSP00000261893.4
LACTB	ENST00000413507.3	c.904A>G	p.Ile302Val	missense_variant	Exon 4 of 5	1		ENSP00000392956.2
RPS27L	ENST00000559763.1	n.96-1621T>C		intron_variant	Intron 1 of 1	3
LACTB	ENST00000557972.1	c.*48A>G		downstream_gene_variant		2		ENSP00000454085.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000171 AC: 42 AN: 246244 AF XY: 0.000149

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000235

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 262 AN: 1456342 Hom.: 0 Cov.: 30 AF XY: 0.000171 AC XY: 124 AN XY: 724612

African (AFR) AF: 0.000752 AC: 25 AN: 33250

American (AMR) AF: 0.000203 AC: 9 AN: 44394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39624

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85564

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53098

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.000194 AC: 215 AN: 1108408

Other (OTH) AF: 0.000133 AC: 8 AN: 60196

GnomAD4 genome AF: 0.000308 AC: 47 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74518

African (AFR) AF: 0.000673 AC: 28 AN: 41586

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.000686 AC: 3

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.904A>G (p.I302V) alteration is located in exon 4 (coding exon 4) of the LACTB gene. This alteration results from a A to G substitution at nucleotide position 904, causing the isoleucine (I) at amino acid position 302 to be replaced by a valine (V). 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	0.065
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.0065	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
PhyloP100		4.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.075
Sift	Benign	0.72	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0010	B;.
Vest4		0.23
MVP		0.40
MPC		0.29
ClinPred		0.010	T
GERP RS		3.8
Varity_R		0.065
gMVP		0.24
Mutation Taster		=92/8	polymorphism

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

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Other links and lift over

dbSNP: rs142381405; hg19: chr15-63419840;