8-120443299-T-G

Variant names:

• chr8-120443299-T-G
• rs2130490602
• NM_014078.6:c.37A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_014078.6(MRPL13):​c.37A>C​(p.Thr13Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T13A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 29)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRPL13 NM_014078.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.47
• Publications: 0 publications found

Genes affected

MRPL13 (HGNC:14278): (mitochondrial ribosomal protein L13) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014078.6. 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
	MRPL13	NM_014078.6	MANE Select	c.37A>C	p.Thr13Pro	missense	Exon 2 of 7	NP_054797.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRPL13	ENST00000306185.8	TSL:1 MANE Select	c.37A>C	p.Thr13Pro	missense	Exon 2 of 7	ENSP00000306548.3	Q9BYD1
	MRPL13	ENST00000518696.5	TSL:1	n.37A>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000428867.1	E5RFI2
	MRPL13	ENST00000862519.1		c.37A>C	p.Thr13Pro	missense	Exon 2 of 8	ENSP00000532578.1

Frequencies

GnomAD3 genomes AF: 0.0000152 AC: 2 AN: 131464 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000162

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.03e-7 AC: 1 AN: 1422128 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 706138

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31382

American (AMR) AF: 0.00 AC: 0 AN: 36684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24450

East Asian (EAS) AF: 0.00 AC: 0 AN: 38730

South Asian (SAS) AF: 0.00 AC: 0 AN: 78216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096204

Other (OTH) AF: 0.00 AC: 0 AN: 58600

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000152 AC: 2 AN: 131532 Hom.: 0 Cov.: 29 AF XY: 0.0000160 AC XY: 1 AN XY: 62594

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000276 AC: 1 AN: 36176

American (AMR) AF: 0.00 AC: 0 AN: 11976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3244

East Asian (EAS) AF: 0.00 AC: 0 AN: 4602

South Asian (SAS) AF: 0.00 AC: 0 AN: 3798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0000162 AC: 1 AN: 61862

Other (OTH) AF: 0.00 AC: 0 AN: 1718

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.44		Gain of glycosylation at T13 (P = 0.07)
MVP		0.88
MPC		0.67
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.65
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2130490602; hg19: chr8-121455539;