2-86210570-C-G

Variant names:

• chr2-86210570-C-G
• rs1455083063
• NM_016622.4:c.469C>G

Variant summary

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

The NM_016622.4(MRPL35):​c.469C>G​(p.Leu157Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MRPL35 NM_016622.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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.469C>G	p.Leu157Val	missense_variant	Exon 4 of 4	ENST00000337109.9	NP_057706.2
MRPL35	NM_001363782.1	c.469C>G	p.Leu157Val	missense_variant	Exon 4 of 5		NP_001350711.1
MRPL35	NM_145644.3	c.469C>G	p.Leu157Val	missense_variant	Exon 4 of 5		NP_663619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL35	ENST00000337109.9	c.469C>G	p.Leu157Val	missense_variant	Exon 4 of 4	1	NM_016622.4	ENSP00000338389.4
MRPL35	ENST00000254644.12	c.469C>G	p.Leu157Val	missense_variant	Exon 4 of 5	1		ENSP00000254644.7
MRPL35	ENST00000409180.1	c.469C>G	p.Leu157Val	missense_variant	Exon 4 of 5	3		ENSP00000386255.1
MRPL35	ENST00000605125.5	c.*36C>G		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000473925.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251330 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135854

Gnomad AFR exome AF: 0.00

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727154

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: 0.0000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.469C>G (p.L157V) alteration is located in exon 4 (coding exon 4) of the MRPL35 gene. This alteration results from a C to G substitution at nucleotide position 469, causing the leucine (L) at amino acid position 157 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	0.25
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.72
MutPred		0.74		Gain of methylation at K156 (P = 0.0329);Gain of methylation at K156 (P = 0.0329);Gain of methylation at K156 (P = 0.0329);
MVP		0.42
MPC		0.35
ClinPred		0.91	D
GERP RS		5.5
Varity_R		0.77
gMVP		0.58

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: rs1455083063; hg19: chr2-86437693;