Variant 2-86210529-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_016622.4(MRPL35):c.428G>A(p.Arg143Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MRPL35
NM_016622.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.46

Variant links:

Genes affected

MRPL35 (HGNC:14489): (mitochondrial ribosomal protein L35) 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. Sequence analysis identified three transcript variants. Pseudogenes corresponding to this gene are found on chromosomes 6p, 10q, and Xp. [provided by RefSeq, Jul 2008]

MRPL35 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2728005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MRPL35	NM_016622.4 linkuse as main transcript	c.428G>A	p.Arg143Gln	missense_variant	4/4	ENST00000337109.9	NP_057706.2
MRPL35	NM_001363782.1 linkuse as main transcript	c.428G>A	p.Arg143Gln	missense_variant	4/5		NP_001350711.1
MRPL35	NM_145644.3 linkuse as main transcript	c.428G>A	p.Arg143Gln	missense_variant	4/5		NP_663619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL35	ENST00000337109.9 linkuse as main transcript	c.428G>A	p.Arg143Gln	missense_variant	4/4	1	NM_016622.4	ENSP00000338389	P1	Q9NZE8-1
MRPL35	ENST00000254644.12 linkuse as main transcript	c.428G>A	p.Arg143Gln	missense_variant	4/5	1		ENSP00000254644		Q9NZE8-2
MRPL35	ENST00000409180.1 linkuse as main transcript	c.428G>A	p.Arg143Gln	missense_variant	4/5	3		ENSP00000386255
MRPL35	ENST00000605125.5 linkuse as main transcript	c.283G>A	p.Asp95Asn	missense_variant	3/3	2		ENSP00000473925

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250248

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1460682

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726626

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

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

Dec 21, 2022

The c.428G>A (p.R143Q) alteration is located in exon 4 (coding exon 4) of the MRPL35 gene. This alteration results from a G to A substitution at nucleotide position 428, causing the arginine (R) at amino acid position 143 to be replaced by a glutamine (Q). 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

0.24

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.34

M_CAP

Benign

0.031

MetaRNN

Benign

0.27

MutationTaster

Benign

1.0

D;D

Vest4

0.13

MVP

0.53

ClinPred

0.98

GERP RS

5.5

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