1-156738523-G-C

Variant names:

• chr1-156738523-G-C
• rs188054107
• NM_145729.3:c.182C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_145729.3(MRPL24):​c.182C>G​(p.Thr61Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,461,846 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (1 hom.)
• Consequence: MRPL24 NM_145729.3 missense, splice_region
• Scores: Splicing: ADA: 0.0005323
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.470

Genes affected

MRPL24 (HGNC:14037): (mitochondrial ribosomal protein L24) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein which is more than twice the size of its E.coli counterpart (EcoL24). Sequence analysis identified two transcript variants that encode the same protein. [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=0.09277642).
• BP6: Variant 1-156738523-G-C is Benign according to our data. Variant chr1-156738523-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3207222.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL24	NM_145729.3	c.182C>G	p.Thr61Arg	missense_variant, splice_region_variant	Exon 2 of 6	ENST00000361531.6	NP_663781.1
MRPL24	NM_024540.4	c.182C>G	p.Thr61Arg	missense_variant, splice_region_variant	Exon 2 of 6		NP_078816.2
MRPL24	XM_011509981.3	c.182C>G	p.Thr61Arg	missense_variant, splice_region_variant	Exon 2 of 6		XP_011508283.1
MRPL24	XM_011509982.3	c.182C>G	p.Thr61Arg	missense_variant, splice_region_variant	Exon 2 of 6		XP_011508284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL24	ENST00000361531.6	c.182C>G	p.Thr61Arg	missense_variant, splice_region_variant	Exon 2 of 6	1	NM_145729.3	ENSP00000354525.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251394 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461846 Hom.: 1 Cov.: 33 AF XY: 0.0000371 AC XY: 27 AN XY: 727230

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: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 22, 2023

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	0.083
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	4.6
DANN	Benign	0.58
DEOGEN2	Benign	0.0056	T;T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.58	.;T;T;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.093	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L;L;.;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.3	N;N;N;N;D
REVEL	Benign	0.17
Sift	Benign	0.74	T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;.;T
Polyphen		0.0020	B;B;.;.;.
Vest4		0.16
MutPred		0.43		Gain of catalytic residue at T61 (P = 0.1448);Gain of catalytic residue at T61 (P = 0.1448);Gain of catalytic residue at T61 (P = 0.1448);Gain of catalytic residue at T61 (P = 0.1448);Gain of catalytic residue at T61 (P = 0.1448);
MVP		0.19
MPC		0.29
ClinPred		0.0089	T
GERP RS		-7.3
Varity_R		0.068
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs188054107; hg19: chr1-156708315; COSMIC: COSV100625869; COSMIC: COSV100625869;