NM_001142568.3:c.445T>G

Variant names:

• chr3-107728804-T-G
• rs2063131364
• NM_001142568.3:c.445T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142568.3(BBX):​c.445T>G​(p.Trp149Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W149R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBX NM_001142568.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46
• Publications: 0 publications found

Genes affected

BBX (HGNC:14422): (BBX high mobility group box domain containing) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within bone development. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBX	NM_001142568.3	c.445T>G	p.Trp149Gly	missense_variant	Exon 6 of 18	ENST00000325805.13	NP_001136040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBX	ENST00000325805.13	c.445T>G	p.Trp149Gly	missense_variant	Exon 6 of 18	1	NM_001142568.3	ENSP00000319974.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.83	.;D;D;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	L;.;L;.;L;.;.;L;.;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-12	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.066	T;T;T;T;D;T;D;T;D;D;T
Polyphen		0.97	D;D;D;.;.;.;.;D;.;.;.
Vest4		0.93
MutPred		0.51		Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);Gain of disorder (P = 0.0274);
MVP		0.92
MPC		0.88
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.95
gMVP		0.73
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs2063131364; hg19: chr3-107447651;