2-224401353-C-T

Variant names:

• chr2-224401353-C-T
• NM_001122779.2:c.416G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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]

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, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM124B	NM_001122779.2	c.416G>A	p.Arg139Lys	missense_variant	Exon 1 of 2	ENST00000409685.4	NP_001116251.1
FAM124B	NM_024785.3	c.416G>A	p.Arg139Lys	missense_variant	Exon 1 of 3		NP_079061.2
FAM124B	XM_047445888.1	c.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
FAM124B	ENST00000409685.4	c.416G>A	p.Arg139Lys	missense_variant	Exon 1 of 2	2	NM_001122779.2	ENSP00000386895.3
FAM124B	ENST00000243806.2	c.416G>A	p.Arg139Lys	missense_variant	Exon 1 of 2	1		ENSP00000243806.2
FAM124B	ENST00000389874.3	c.416G>A	p.Arg139Lys	missense_variant	Exon 1 of 3	1		ENSP00000374524.3

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

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

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;