15-63127547-G-C

Variant names:

• chr15-63127547-G-C
• rs375272227
• NM_032857.5:c.810G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032857.5(LACTB):​c.810G>C​(p.Glu270Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,598 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LACTB NM_032857.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.06

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02522096).
• BP6: Variant 15-63127547-G-C is Benign according to our data. Variant chr15-63127547-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3289834.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LACTB	NM_032857.5	c.810G>C	p.Glu270Asp	missense_variant	Exon 4 of 6	ENST00000261893.9	NP_116246.2
LACTB	NM_171846.4	c.810G>C	p.Glu270Asp	missense_variant	Exon 4 of 5		NP_741982.1
LACTB	NM_001288585.2	c.810G>C	p.Glu270Asp	missense_variant	Exon 4 of 5		NP_001275514.1
LACTB	XM_047432128.1	c.810G>C	p.Glu270Asp	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.810G>C	p.Glu270Asp	missense_variant	Exon 4 of 6	1	NM_032857.5	ENSP00000261893.4
LACTB	ENST00000413507.3	c.810G>C	p.Glu270Asp	missense_variant	Exon 4 of 5	1		ENSP00000392956.2
LACTB	ENST00000557972.1	c.333G>C	p.Glu111Asp	missense_variant	Exon 3 of 3	2		ENSP00000454085.1
RPS27L	ENST00000559763.1	n.96-1527C>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461598 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727078

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 08, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.72
DANN	Benign	0.55
DEOGEN2	Benign	0.0053	T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.040	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.86	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.12
MutPred		0.25		Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;
MVP		0.16
MPC		0.31
ClinPred		0.045	T
GERP RS		-5.5
Varity_R		0.027
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375272227; hg19: chr15-63419746;