2-86206204-C-G

Position:

• chr2-86206204-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016622.4(MRPL35):​c.142C>G​(p.His48Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRPL35 NM_016622.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.691

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14970878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRPL35	NM_016622.4	c.142C>G	p.His48Asp	missense_variant	2/4	ENST00000337109.9	NP_057706.2
MRPL35	NM_001363782.1	c.142C>G	p.His48Asp	missense_variant	2/5		NP_001350711.1
MRPL35	NM_145644.3	c.142C>G	p.His48Asp	missense_variant	2/5		NP_663619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRPL35	ENST00000337109.9	c.142C>G	p.His48Asp	missense_variant	2/4	1	NM_016622.4	ENSP00000338389.4
MRPL35	ENST00000254644.12	c.142C>G	p.His48Asp	missense_variant	2/5	1		ENSP00000254644.7
MRPL35	ENST00000409180.1	c.142C>G	p.His48Asp	missense_variant	2/5	3		ENSP00000386255.1
MRPL35	ENST00000605125.5	c.142C>G	p.His48Asp	missense_variant	2/3	2		ENSP00000473925.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2024

The c.142C>G (p.H48D) alteration is located in exon 2 (coding exon 2) of the MRPL35 gene. This alteration results from a C to G substitution at nucleotide position 142, causing the histidine (H) at amino acid position 48 to be replaced by an aspartic acid (D). 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	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.0057	.;.;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;.;N;N
REVEL	Benign	0.040
Sift	Benign	0.22	T;.;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.023	.;.;B;.
Vest4		0.49
MutPred		0.34		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.21
MPC		0.25
ClinPred		0.035	T
GERP RS		2.6
Varity_R		0.047
gMVP		0.36

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: chr2-86433327;