21-25601427-A-G

Variant names:

• chr21-25601427-A-G
• NM_017446.4:c.461T>C

Variant summary

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

The NM_017446.4(MRPL39):​c.461T>C​(p.Ile154Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MRPL39 NM_017446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

Genes affected

MRPL39 (HGNC:14027): (mitochondrial ribosomal protein L39) 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. Two transcript variants encoding distinct isoforms have been described. A pseudogene corresponding to this gene is found on chromosome 5q. [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
MRPL39	NM_017446.4	c.461T>C	p.Ile154Thr	missense_variant	Exon 4 of 10	ENST00000352957.9	NP_059142.3
MRPL39	NM_080794.4	c.461T>C	p.Ile154Thr	missense_variant	Exon 4 of 11		NP_542984.3
MRPL39	XM_006724026.5	c.461T>C	p.Ile154Thr	missense_variant	Exon 4 of 10		XP_006724089.1
MRPL39	XM_011529651.3	c.335T>C	p.Ile112Thr	missense_variant	Exon 4 of 10		XP_011527953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRPL39	ENST00000352957.9	c.461T>C	p.Ile154Thr	missense_variant	Exon 4 of 10	1	NM_017446.4	ENSP00000284967.7
MRPL39	ENST00000307301.11	c.461T>C	p.Ile154Thr	missense_variant	Exon 4 of 11	5		ENSP00000305682.7
MRPL39	ENST00000419219.1	c.461T>C	p.Ile154Thr	missense_variant	Exon 4 of 8	5		ENSP00000404426.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.461T>C (p.I154T) alteration is located in exon 4 (coding exon 4) of the MRPL39 gene. This alteration results from a T to C substitution at nucleotide position 461, causing the isoleucine (I) at amino acid position 154 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	Benign	0.20
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.41	B;P;.
Vest4		0.78
MutPred		0.54		Gain of phosphorylation at I154 (P = 0.0805);Gain of phosphorylation at I154 (P = 0.0805);Gain of phosphorylation at I154 (P = 0.0805);
MVP		0.83
MPC		0.075
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.44
gMVP		0.50

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: chr21-26973739;