12-27737586-C-A

Position:

chr12-27737586-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000081029.8(MRPS35):c.680C>A(p.Thr227Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000751 in 1,610,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 1 hom. )

Consequence

MRPS35
ENST00000081029.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.64

Variant links:

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]

MRPS35 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15589166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPS35	NM_021821.4 linkuse as main transcript	c.680C>A	p.Thr227Lys	missense_variant	7/8	ENST00000081029.8	NP_068593.2
MRPS35	NM_001190864.2 linkuse as main transcript	c.570C>A	p.Asn190Lys	missense_variant	6/7		NP_001177793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPS35	ENST00000081029.8 linkuse as main transcript	c.680C>A	p.Thr227Lys	missense_variant	7/8	1	NM_021821.4	ENSP00000081029	P1	P82673-1
MRPS35	ENST00000538315.5 linkuse as main transcript	c.570C>A	p.Asn190Lys	missense_variant	6/7	2		ENSP00000445390		P82673-2
MRPS35	ENST00000542791.1 linkuse as main transcript	c.110-17595C>A		intron_variant		3		ENSP00000437991
MRPS35	ENST00000542199.1 linkuse as main transcript	c.*240C>A		3_prime_UTR_variant, NMD_transcript_variant	8/8	3		ENSP00000442137

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00101

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000415

AC:

104

AN:

250866

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000778

AC:

1135

AN:

1458054

Hom.:

Cov.:

AF XY:

0.000744

AC XY:

540

AN XY:

725614

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000990

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.000486

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00101

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000529

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000395

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.680C>A (p.T227K) alteration is located in exon 7 (coding exon 7) of the MRPS35 gene. This alteration results from a C to A substitution at nucleotide position 680, causing the threonine (T) at amino acid position 227 to be replaced by a lysine (K). 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.20

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.52

MutationTaster

Benign

1.0

D;N

PROVEAN

Benign

1.3

REVEL

Benign

0.047

Sift

Benign

0.27

Sift4G

Benign

0.071

Vest4

0.32

MutPred

0.29

Loss of sheet (P = 0.003);

MVP

0.70

ClinPred

0.73

GERP RS

5.3

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over