2-86207275-C-T

Variant names:

• chr2-86207275-C-T
• NM_016622.4:c.326C>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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23

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]

ACMG classification

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
MRPL35	NM_016622.4	c.326C>T	p.Ala109Val	missense_variant	Exon 3 of 4	ENST00000337109.9	NP_057706.2
MRPL35	NM_001363782.1	c.326C>T	p.Ala109Val	missense_variant	Exon 3 of 5		NP_001350711.1
MRPL35	NM_145644.3	c.326C>T	p.Ala109Val	missense_variant	Exon 3 of 5		NP_663619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL35	ENST00000337109.9	c.326C>T	p.Ala109Val	missense_variant	Exon 3 of 4	1	NM_016622.4	ENSP00000338389.4
MRPL35	ENST00000254644.12	c.326C>T	p.Ala109Val	missense_variant	Exon 3 of 5	1		ENSP00000254644.7
MRPL35	ENST00000409180.1	c.326C>T	p.Ala109Val	missense_variant	Exon 3 of 5	3		ENSP00000386255.1
MRPL35	ENST00000605125.5	c.233+980C>T		intron_variant	Intron 2 of 2	2		ENSP00000473925.1

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

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

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;