chr2-86206268-G-A

Variant names:

• chr2-86206268-G-A
• rs761730542
• NM_016622.4:c.206G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016622.4(MRPL35):​c.206G>A​(p.Cys69Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C69R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRPL35 NM_016622.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.252
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037385106).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016622.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL35	NM_016622.4	MANE Select	c.206G>A	p.Cys69Tyr	missense	Exon 2 of 4	NP_057706.2
	MRPL35	NM_001363782.1		c.206G>A	p.Cys69Tyr	missense	Exon 2 of 5	NP_001350711.1	D3YTC1
	MRPL35	NM_145644.3		c.206G>A	p.Cys69Tyr	missense	Exon 2 of 5	NP_663619.1	Q9NZE8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL35	ENST00000337109.9	TSL:1 MANE Select	c.206G>A	p.Cys69Tyr	missense	Exon 2 of 4	ENSP00000338389.4	Q9NZE8-1
	MRPL35	ENST00000254644.12	TSL:1	c.206G>A	p.Cys69Tyr	missense	Exon 2 of 5	ENSP00000254644.7	Q9NZE8-2
	MRPL35	ENST00000409180.1	TSL:3	c.206G>A	p.Cys69Tyr	missense	Exon 2 of 5	ENSP00000386255.1	D3YTC1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251070 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461374 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727008

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111606

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.5
DANN	Benign	0.28
DEOGEN2	Benign	0.00076	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.25
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.017
Sift	Benign	0.86	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.31		Gain of helix (P = 0.132)
MVP		0.076
MPC		0.24
ClinPred		0.0057	T
GERP RS		2.2
Varity_R		0.025
gMVP		0.36
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs761730542; hg19: chr2-86433391; COSMIC: COSV105836755;