2-224379666-G-T

Variant names:

• chr2-224379666-G-T
• rs1459710314
• NM_001122779.2:c.1275C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001122779.2(FAM124B):​c.1275C>A​(p.Asp425Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,388 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: FAM124B NM_001122779.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.97

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033397168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM124B	NM_001122779.2	c.1275C>A	p.Asp425Glu	missense_variant	Exon 2 of 2	ENST00000409685.4	NP_001116251.1
FAM124B	NM_024785.3	c.*581C>A		3_prime_UTR_variant	Exon 3 of 3		NP_079061.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM124B	ENST00000409685.4	c.1275C>A	p.Asp425Glu	missense_variant	Exon 2 of 2	2	NM_001122779.2	ENSP00000386895.3
FAM124B	ENST00000389874	c.*581C>A		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000374524.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399388 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 690196

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: 9.27e-7

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

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1275C>A (p.D425E) alteration is located in exon 2 (coding exon 2) of the FAM124B gene. This alteration results from a C to A substitution at nucleotide position 1275, causing the aspartic acid (D) at amino acid position 425 to be replaced by a glutamic acid (E). 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	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.011
DANN	Benign	0.86
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.73	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.026
Sift	Benign	0.20	T
Sift4G	Benign	0.25	T
Polyphen		0.037	B
Vest4		0.022
MutPred		0.15		Gain of ubiquitination at K430 (P = 0.0804);
MVP		0.30
MPC		0.10
ClinPred		0.078	T
GERP RS		-5.5
Varity_R		0.039
gMVP		0.13

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

Other links and lift over

dbSNP: rs1459710314; hg19: chr2-225244383;