1-20501054-C-T

Variant summary

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

The NM_024544.3(MUL1):​c.695G>A​(p.Arg232Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

MUL1
NM_024544.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.635
Variant links:
Genes affected
MUL1 (HGNC:25762): (mitochondrial E3 ubiquitin protein ligase 1) Enables several functions, including p53 binding activity; ubiquitin protein ligase binding activity; and ubiquitin-like protein transferase activity. Involved in several processes, including negative regulation of defense response; positive regulation of cellular protein metabolic process; and regulation of mitochondrion organization. Located in several cellular components, including mitochondrion; neuronal cell body; and peroxisome. Is integral component of mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.009372652).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MUL1NM_024544.3 linkc.695G>A p.Arg232Lys missense_variant 4/4 ENST00000264198.5 NP_078820.2
MUL1XM_011542137.3 linkc.578G>A p.Arg193Lys missense_variant 4/4 XP_011540439.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MUL1ENST00000264198.5 linkc.695G>A p.Arg232Lys missense_variant 4/41 NM_024544.3 ENSP00000264198.3 Q969V5

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152254
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000215
AC:
54
AN:
251310
Hom.:
1
AF XY:
0.000250
AC XY:
34
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.000596
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000261
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000211
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000115
AC:
168
AN:
1461792
Hom.:
1
Cov.:
32
AF XY:
0.000117
AC XY:
85
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000425
Gnomad4 ASJ exome
AF:
0.000918
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000908
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152372
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
8
AN XY:
74510
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000243
Hom.:
0
Bravo
AF:
0.000136
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000239
AC:
29
EpiCase
AF:
0.000545
EpiControl
AF:
0.000415

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 16, 2024The c.695G>A (p.R232K) alteration is located in exon 4 (coding exon 4) of the MUL1 gene. This alteration results from a G to A substitution at nucleotide position 695, causing the arginine (R) at amino acid position 232 to be replaced by a lysine (K). 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
0.063
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.80
CADD
Benign
6.9
DANN
Benign
0.88
DEOGEN2
Benign
0.012
T
Eigen
Benign
-0.88
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.0030
T
MetaRNN
Benign
0.0094
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.47
N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.48
N
REVEL
Benign
0.018
Sift
Benign
0.62
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.026
MVP
0.055
MPC
0.36
ClinPred
0.0056
T
GERP RS
2.3
Varity_R
0.044
gMVP
0.24

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: rs143833510; hg19: chr1-20827547; API