2-86207275-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016622.4(MRPL35):​c.326C>T​(p.Ala109Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MRPL35
NM_016622.4 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.23
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MRPL35NM_016622.4 linkc.326C>T p.Ala109Val missense_variant Exon 3 of 4 ENST00000337109.9 NP_057706.2 Q9NZE8-1
MRPL35NM_001363782.1 linkc.326C>T p.Ala109Val missense_variant Exon 3 of 5 NP_001350711.1
MRPL35NM_145644.3 linkc.326C>T p.Ala109Val missense_variant Exon 3 of 5 NP_663619.1 Q9NZE8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MRPL35ENST00000337109.9 linkc.326C>T p.Ala109Val missense_variant Exon 3 of 4 1 NM_016622.4 ENSP00000338389.4 Q9NZE8-1
MRPL35ENST00000254644.12 linkc.326C>T p.Ala109Val missense_variant Exon 3 of 5 1 ENSP00000254644.7 Q9NZE8-2
MRPL35ENST00000409180.1 linkc.326C>T p.Ala109Val missense_variant Exon 3 of 5 3 ENSP00000386255.1 D3YTC1
MRPL35ENST00000605125.5 linkc.233+980C>T intron_variant Intron 2 of 2 2 ENSP00000473925.1 S4R348

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461718
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 03, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.326C>T (p.A109V) alteration is located in exon 3 (coding exon 3) of the MRPL35 gene. This alteration results from a C to T substitution at nucleotide position 326, causing the alanine (A) at amino acid position 109 to be replaced by a valine (V). 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
0.33
BayesDel_addAF
Benign
-0.084
T
BayesDel_noAF
Benign
-0.36
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.068
.;T;.
Eigen
Pathogenic
0.68
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.023
T
MetaRNN
Uncertain
0.56
D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
M;M;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.0
D;D;D
REVEL
Benign
0.24
Sift
Uncertain
0.0050
D;D;D
Sift4G
Uncertain
0.010
D;D;D
Polyphen
0.94
.;P;.
Vest4
0.65
MutPred
0.57
Gain of methylation at K108 (P = 0.0484);Gain of methylation at K108 (P = 0.0484);Gain of methylation at K108 (P = 0.0484);
MVP
0.32
MPC
0.59
ClinPred
0.96
D
GERP RS
5.1
Varity_R
0.37
gMVP
0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-86434398; API