2-224401353-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001122779.2(FAM124B):​c.416G>A​(p.Arg139Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FAM124B
NM_001122779.2 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.61
Variant links:
Genes affected
FAM124B (HGNC:26224): (family with sequence similarity 124 member B) Located in mitochondrion and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAM124BNM_001122779.2 linkc.416G>A p.Arg139Lys missense_variant Exon 1 of 2 ENST00000409685.4 NP_001116251.1 Q9H5Z6-1
FAM124BNM_024785.3 linkc.416G>A p.Arg139Lys missense_variant Exon 1 of 3 NP_079061.2 Q9H5Z6-2
FAM124BXM_047445888.1 linkc.416G>A p.Arg139Lys missense_variant Exon 1 of 2 XP_047301844.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAM124BENST00000409685.4 linkc.416G>A p.Arg139Lys missense_variant Exon 1 of 2 2 NM_001122779.2 ENSP00000386895.3 Q9H5Z6-1
FAM124BENST00000243806.2 linkc.416G>A p.Arg139Lys missense_variant Exon 1 of 2 1 ENSP00000243806.2 Q9H5Z6-2
FAM124BENST00000389874.3 linkc.416G>A p.Arg139Lys missense_variant Exon 1 of 3 1 ENSP00000374524.3 Q9H5Z6-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 23, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.416G>A (p.R139K) alteration is located in exon 1 (coding exon 1) of the FAM124B gene. This alteration results from a G to A substitution at nucleotide position 416, causing the arginine (R) at amino acid position 139 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
Uncertain
0.42
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
.;T;.
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.86
.;D;D
M_CAP
Benign
0.022
T
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Uncertain
-0.065
T
MutationAssessor
Pathogenic
3.1
M;M;M
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-2.8
D;D;D
REVEL
Uncertain
0.45
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
0.94
P;D;P
Vest4
0.81
MutPred
0.87
Gain of ubiquitination at R139 (P = 0.0211);Gain of ubiquitination at R139 (P = 0.0211);Gain of ubiquitination at R139 (P = 0.0211);
MVP
0.83
MPC
0.53
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.76
gMVP
0.74

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: chr2-225266070; API