Genetic Variant FAM124B:p.Tyr236Asn (chr2-224401063-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001122779.2(FAM124B):c.706T>A(p.Tyr236Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,454,914 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: 0.0000021 ( 0 hom. )

Consequence

FAM124B
NM_001122779.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.88

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM124B	NM_001122779.2 link	c.706T>A	p.Tyr236Asn	missense_variant	Exon 1 of 2	ENST00000409685.4	NP_001116251.1	Q9H5Z6-1
FAM124B	NM_024785.3 link	c.706T>A	p.Tyr236Asn	missense_variant	Exon 1 of 3		NP_079061.2	Q9H5Z6-2
FAM124B	XM_047445888.1 link	c.706T>A	p.Tyr236Asn	missense_variant	Exon 1 of 2		XP_047301844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM124B	ENST00000409685.4 link	c.706T>A	p.Tyr236Asn	missense_variant	Exon 1 of 2	2	NM_001122779.2	ENSP00000386895.3	Q9H5Z6-1
FAM124B	ENST00000243806.2 link	c.706T>A	p.Tyr236Asn	missense_variant	Exon 1 of 2	1		ENSP00000243806.2	Q9H5Z6-2
FAM124B	ENST00000389874.3 link	c.706T>A	p.Tyr236Asn	missense_variant	Exon 1 of 3	1		ENSP00000374524.3	Q9H5Z6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248364

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1454914

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722598

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.706T>A (p.Y236N) alteration is located in exon 1 (coding exon 1) of the FAM124B gene. This alteration results from a T to A substitution at nucleotide position 706, causing the tyrosine (Y) at amino acid position 236 to be replaced by an asparagine (N). 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

Pathogenic

0.57

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.8

M;M;M

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.029

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.96

D;D;D

Vest4

0.76

MutPred

0.44

Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);Gain of disorder (P = 0.0135);

MVP

0.79

MPC

0.67

ClinPred

0.99

GERP RS

5.8

Varity_R

0.51

gMVP

0.62

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