6-152992950-C-T

Variant names:

• chr6-152992950-C-T
• NM_019041.7:c.712G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_019041.7(MTRF1L):​c.712G>A​(p.Asp238Asn) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTRF1L NM_019041.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

Genes affected

MTRF1L (HGNC:21051): (mitochondrial translation release factor 1 like) The protein encoded by this gene plays a role in mitochondrial translation termination, and is thought to be a release factor that is involved in the dissociation of the complete protein from the final tRNA, the ribosome, and the cognate mRNA. This protein acts upon UAA and UAG stop codons, but has no in vitro activity against UGA, which encodes tryptophan in human mitochondrion, or, the mitochondrial non-cognate stop codons, AGA and AGG. This protein shares sequence similarity to bacterial release factors. Pseudogenes of this gene are found on chromosomes 4, 8, and 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRF1L	NM_019041.7	c.712G>A	p.Asp238Asn	missense_variant	Exon 5 of 7	ENST00000367233.10	NP_061914.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRF1L	ENST00000367233.10	c.712G>A	p.Asp238Asn	missense_variant	Exon 5 of 7	1	NM_019041.7	ENSP00000356202.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.712G>A (p.D238N) alteration is located in exon 5 (coding exon 5) of the MTRF1L gene. This alteration results from a G to A substitution at nucleotide position 712, causing the aspartic acid (D) at amino acid position 238 to be replaced by an asparagine (N). 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	0.42
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;T;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.7	.;H;H;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		0.99, 0.98, 0.96	.;D;D;D;.
Vest4		0.73, 0.74
MutPred		0.92		.;Gain of MoRF binding (P = 0.0314);Gain of MoRF binding (P = 0.0314);.;.;
MVP		0.51
MPC		1.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.72
gMVP		0.78

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: chr6-153314085;