12-27710859-C-A

Position:

• chr12-27710859-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021821.4(MRPS35):​c.16C>A​(p.Leu6Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00455 in 1,608,568 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.025 (139 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (155 hom.)
• Consequence: MRPS35 NM_021821.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.312

Genes affected

MRPS35 (HGNC:16635): (mitochondrial ribosomal protein S35) 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 28S subunit protein that has had confusing nomenclature in the literature. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. Pseudogenes corresponding to this gene are found on chromosomes 3p, 5q, and 10q. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020008683).
• BP6: Variant 12-27710859-C-A is Benign according to our data. Variant chr12-27710859-C-A is described in ClinVar as [Benign]. Clinvar id is 784234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS35	NM_021821.4	c.16C>A	p.Leu6Ile	missense_variant	1/8	ENST00000081029.8	NP_068593.2
MRPS35	NM_001190864.2	c.16C>A	p.Leu6Ile	missense_variant	1/7		NP_001177793.1
MRPS35	XM_017019780.2	c.16C>A	p.Leu6Ile	missense_variant	1/6		XP_016875269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS35	ENST00000081029.8	c.16C>A	p.Leu6Ile	missense_variant	1/8	1	NM_021821.4	ENSP00000081029.3

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3764 AN: 152214 Hom.: 139 Cov.: 33

Gnomad AFR AF: 0.0859

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.00617 AC: 1503 AN: 243452 Hom.: 54 AF XY: 0.00447 AC XY: 594 AN XY: 132772

Gnomad AFR exome AF: 0.0864

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00245 AC: 3561 AN: 1456236 Hom.: 155 Cov.: 31 AF XY: 0.00205 AC XY: 1486 AN XY: 724752

Gnomad4 AFR exome AF: 0.0857

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.00518

GnomAD4 genome AF: 0.0247 AC: 3762 AN: 152332 Hom.: 139 Cov.: 33 AF XY: 0.0235 AC XY: 1750 AN XY: 74502

Gnomad4 AFR AF: 0.0856

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00251 Hom.: 15

Bravo AF: 0.0277

ESP6500AA AF: 0.0729 AC: 321

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00728 AC: 884

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	2.6
DANN	Benign	0.96
DEOGEN2	Benign	0.010	T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.50	T;T;T
MetaRNN	Benign	0.0020	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.43	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.15	T;T;D
Sift4G	Benign	0.25	T;T;T
Polyphen		0.036	B;B;.
Vest4		0.36
MVP		0.27
MPC		0.072
ClinPred		0.0051	T
GERP RS		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.085
gMVP		0.21

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: rs35475802; hg19: chr12-27863792; COSMIC: COSV50012079; COSMIC: COSV50012079;