3-107728804-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001142568.3(BBX):​c.445T>C​(p.Trp149Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,386 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: 0.0000034 (0 hom.)
• Consequence: BBX NM_001142568.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142568.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBX	NM_001142568.3	MANE Select	c.445T>C	p.Trp149Arg	missense	Exon 6 of 18	NP_001136040.1	Q8WY36-1
	BBX	NM_020235.7		c.445T>C	p.Trp149Arg	missense	Exon 6 of 17	NP_064620.2
	BBX	NM_001276286.2		c.445T>C	p.Trp149Arg	missense	Exon 6 of 17	NP_001263215.1	Q8WY36-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBX	ENST00000325805.13	TSL:1 MANE Select	c.445T>C	p.Trp149Arg	missense	Exon 6 of 18	ENSP00000319974.8	Q8WY36-1
	BBX	ENST00000415149.6	TSL:1	c.445T>C	p.Trp149Arg	missense	Exon 6 of 17	ENSP00000408358.2	Q8WY36-2
	BBX	ENST00000416476.6	TSL:1	c.445T>C	p.Trp149Arg	missense	Exon 6 of 17	ENSP00000403860.2	Q8WY36-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461386 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726972

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111762

Other (OTH) AF: 0.0000331 AC: 2 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.48		Gain of disorder (P = 0.0223)
MVP		0.96
MPC		0.88
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.92
gMVP		0.76
Mutation Taster		=17/83	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;