chr17-47827092-A-G

Variant names:

• chr17-47827092-A-G
• NM_145255.4:c.335T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145255.4(MRPL10):​c.335T>C​(p.Met112Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL10 NM_145255.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.49

Genes affected

MRPL10 (HGNC:14055): (mitochondrial ribosomal protein L10) 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 that encode two different isoforms. A pseudogene corresponding to this gene is found on chromosome 5q. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38868606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRPL10	NM_145255.4	c.335T>C	p.Met112Thr	missense_variant	Exon 3 of 5	ENST00000351111.7	NP_660298.2
MRPL10	NM_148887.3	c.365T>C	p.Met122Thr	missense_variant	Exon 4 of 6		NP_683685.1
MRPL10	XM_024450575.2	c.365T>C	p.Met122Thr	missense_variant	Exon 4 of 6		XP_024306343.1
MRPL10	NR_037575.2	n.514T>C		non_coding_transcript_exon_variant	Exon 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL10	ENST00000351111.7	c.335T>C	p.Met112Thr	missense_variant	Exon 3 of 5	1	NM_145255.4	ENSP00000324100.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1461760 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60390

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 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.365T>C (p.M122T) alteration is located in exon 4 (coding exon 3) of the MRPL10 gene. This alteration results from a T to C substitution at nucleotide position 365, causing the methionine (M) at amino acid position 122 to be replaced by a threonine (T). 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	Uncertain	0.45
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;.;.
PhyloP100		8.5
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.38	B;.;.
Vest4		0.38
MutPred		0.68		Loss of MoRF binding (P = 0.0793);.;.;
MVP		0.38
MPC		0.24
ClinPred		0.86	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.70
Mutation Taster		=48/52	disease causing

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

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Other links and lift over

hg19: chr17-45904458;