22-19433328-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001318151.2(MRPL40):​c.-16C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000962 in 1,611,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

MRPL40
NM_001318151.2 5_prime_UTR_premature_start_codon_gain

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.537
Variant links:
Genes affected
MRPL40 (HGNC:14491): (mitochondrial ribosomal protein L40) 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. Deletions in this gene may contribute to the etiology of velo-cardio-facial syndrome and DiGeorge syndrome. [provided by RefSeq, Jul 2008]
HIRA (HGNC:4916): (histone cell cycle regulator) This gene encodes a histone chaperone that preferentially places the variant histone H3.3 in nucleosomes. Orthologs of this gene in yeast, flies, and plants are necessary for the formation of transcriptionally silent heterochomatin. This gene plays an important role in the formation of the senescence-associated heterochromatin foci. These foci likely mediate the irreversible cell cycle changes that occur in senescent cells. It is considered the primary candidate gene in some haploinsufficiency syndromes such as DiGeorge syndrome, and insufficient production of the gene may disrupt normal embryonic development. [provided by RefSeq, Jul 2008]
C22orf39 (HGNC:27012): (chromosome 22 open reading frame 39)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.016040832).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MRPL40NM_003776.4 linkc.117C>G p.Phe39Leu missense_variant Exon 2 of 4 ENST00000333130.4 NP_003767.2 Q9NQ50
MRPL40NM_001318151.2 linkc.-16C>G 5_prime_UTR_premature_start_codon_gain_variant Exon 2 of 4 NP_001305080.1
MRPL40NM_001318151.2 linkc.-16C>G 5_prime_UTR_variant Exon 2 of 4 NP_001305080.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MRPL40ENST00000333130.4 linkc.117C>G p.Phe39Leu missense_variant Exon 2 of 4 1 NM_003776.4 ENSP00000333401.3 Q9NQ50

Frequencies

GnomAD3 genomes
AF:
0.000499
AC:
76
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00176
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000111
AC:
28
AN:
251370
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00160
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000541
AC:
79
AN:
1459192
Hom.:
0
Cov.:
28
AF XY:
0.0000441
AC XY:
32
AN XY:
726064
show subpopulations
Gnomad4 AFR exome
AF:
0.00203
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.01e-7
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000499
AC:
76
AN:
152306
Hom.:
0
Cov.:
33
AF XY:
0.000457
AC XY:
34
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.00176
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000304
Hom.:
0
Bravo
AF:
0.000552
ESP6500AA
AF:
0.00159
AC:
7
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000132
AC:
16

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 06, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.117C>G (p.F39L) alteration is located in exon 2 (coding exon 2) of the MRPL40 gene. This alteration results from a C to G substitution at nucleotide position 117, causing the phenylalanine (F) at amino acid position 39 to be replaced by a leucine (L). 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
Pathogenic
0.68
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
17
DANN
Benign
0.93
DEOGEN2
Benign
0.0058
T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.35
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.016
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.058
Sift
Benign
0.56
T
Sift4G
Benign
0.61
T
Polyphen
0.012
B
Vest4
0.32
MutPred
0.25
Gain of disorder (P = 0.0497);
MVP
0.21
MPC
0.094
ClinPred
0.018
T
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.16
gMVP
0.16

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149859647; hg19: chr22-19420851; API