10-122849268-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152644.3(FAM24B):c.264C>G(p.Cys88Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000423 in 1,417,774 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: 0.0000042 (0 hom.)
• Consequence: FAM24B NM_152644.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

Genes affected

FAM24B (HGNC:23475): (family with sequence similarity 24 member B) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

FAM24B-CUZD1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM24B	NM_152644.3	c.264C>G	p.Cys88Trp	missense_variant	4/4	ENST00000368898.8
FAM24B-CUZD1	NR_037915.1	n.300-3048C>G		intron_variant, non_coding_transcript_variant
FAM24B	NM_001204364.1	c.264C>G	p.Cys88Trp	missense_variant	4/4
FAM24B	NR_037911.1	n.471C>G		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM24B	ENST00000368898.8	c.264C>G	p.Cys88Trp	missense_variant	4/4	1	NM_152644.3	P1
FAM24B	ENST00000368896.1	c.264C>G	p.Cys88Trp	missense_variant	4/4	2		P1
FAM24B	ENST00000462859.5	n.471C>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000423 AC: 6 AN: 1417774 Hom.: 0 Cov.: 30 AF XY: 0.00000428 AC XY: 3 AN XY: 700198

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: 0.00000553

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.264C>G (p.C88W) alteration is located in exon 4 (coding exon 2) of the FAM24B gene. This alteration results from a C to G substitution at nucleotide position 264, causing the cysteine (C) at amino acid position 88 to be replaced by a tryptophan (W). 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	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.12	N
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.53	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-9.6	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.51		Gain of solvent accessibility (P = 0.0133);Gain of solvent accessibility (P = 0.0133);
MVP		0.45
MPC		1.1
ClinPred		0.99	D
GERP RS		2.0
Varity_R		0.34
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs758502475; hg19: chr10-124608784;