10-124623601-A-G

Position:

• chr10-124623601-A-G

Variant summary

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

The NM_014661.4(FAM53B):​c.910T>C​(p.Cys304Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAM53B NM_014661.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

Genes affected

FAM53B (HGNC:28968): (family with sequence similarity 53 member B) Involved in positive regulation of canonical Wnt signaling pathway. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

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=0.06649637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM53B	NM_014661.4	c.910T>C	p.Cys304Arg	missense_variant	5/5	ENST00000337318.8	NP_055476.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM53B	ENST00000337318.8	c.910T>C	p.Cys304Arg	missense_variant	5/5	1	NM_014661.4	ENSP00000338532	P1
	ENST00000621254.1	n.249A>G		non_coding_transcript_exon_variant	1/1
FAM53B	ENST00000392754.7	c.910T>C	p.Cys304Arg	missense_variant	5/5	2		ENSP00000376509	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000839 AC: 2 AN: 238338 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

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

Feb 17, 2024

The c.910T>C (p.C304R) alteration is located in exon 5 (coding exon 4) of the FAM53B gene. This alteration results from a T to C substitution at nucleotide position 910, causing the cysteine (C) at amino acid position 304 to be replaced by an arginine (R). 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	0.17
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.60	.;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.025
Sift	Benign	0.18	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0030	B;B
Vest4		0.092
MutPred		0.29		Gain of MoRF binding (P = 0.0284);Gain of MoRF binding (P = 0.0284);
MVP		0.22
MPC		1.3
ClinPred		0.24	T
GERP RS		4.0
Varity_R		0.20
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781622801; hg19: chr10-126312170;