Genetic Variant FAM124B:p.Glu360Lys (chr2-224379863-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001122779.2(FAM124B):c.1078G>A(p.Glu360Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000277 in 1,552,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

FAM124B
NM_001122779.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18

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]

FAM124B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM124B	NM_001122779.2 link	c.1078G>A	p.Glu360Lys	missense_variant	Exon 2 of 2	ENST00000409685.4	NP_001116251.1	Q9H5Z6-1
FAM124B	NM_024785.3 link	c.*384G>A		3_prime_UTR_variant	Exon 3 of 3		NP_079061.2	Q9H5Z6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM124B	ENST00000409685.4 link	c.1078G>A	p.Glu360Lys	missense_variant	Exon 2 of 2	2	NM_001122779.2	ENSP00000386895.3		Q9H5Z6-1
FAM124B	ENST00000389874 link	c.*384G>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000374524.3		Q9H5Z6-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000506

AC:

AN:

158106

Hom.:

AF XY:

0.0000959

AC XY:

AN XY:

83462

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000487

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000286

AC:

AN:

1399796

Hom.:

Cov.:

AF XY:

0.0000348

AC XY:

AN XY:

690398

show subpopulations

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000232

Gnomad4 OTH exome

AF:

0.000120

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.0000391

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1078G>A (p.E360K) alteration is located in exon 2 (coding exon 2) of the FAM124B gene. This alteration results from a G to A substitution at nucleotide position 1078, causing the glutamic acid (E) at amino acid position 360 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

0.34

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.66

MVP

0.74

MPC

0.56

ClinPred

0.65

GERP RS

5.9

Varity_R

0.51

gMVP

0.72

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over