3-107716668-C-T

Variant names:

• chr3-107716668-C-T
• rs199641554
• NM_001142568.3:c.224C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001142568.3(BBX):​c.224C>T​(p.Ser75Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,613,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: BBX NM_001142568.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032965332).

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.224C>T	p.Ser75Leu	missense	Exon 5 of 18	NP_001136040.1	Q8WY36-1
	BBX	NM_020235.7		c.224C>T	p.Ser75Leu	missense	Exon 5 of 17	NP_064620.2
	BBX	NM_001276286.2		c.224C>T	p.Ser75Leu	missense	Exon 5 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.224C>T	p.Ser75Leu	missense	Exon 5 of 18	ENSP00000319974.8	Q8WY36-1
	BBX	ENST00000415149.6	TSL:1	c.224C>T	p.Ser75Leu	missense	Exon 5 of 17	ENSP00000408358.2	Q8WY36-2
	BBX	ENST00000416476.6	TSL:1	c.224C>T	p.Ser75Leu	missense	Exon 5 of 17	ENSP00000403860.2	Q8WY36-3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000299 AC: 75 AN: 251100 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000120 AC: 176 AN: 1461556 Hom.: 0 Cov.: 30 AF XY: 0.000100 AC XY: 73 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.000515 AC: 23 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00402 AC: 105 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111794

Other (OTH) AF: 0.000265 AC: 16 AN: 60364

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.000131 AC: 2 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000526 Hom.: 0

Bravo AF: 0.000223

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

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	Benign	0.14
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.033	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.0	L
PhyloP100		4.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.71
MPC		0.61
ClinPred		0.12	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.34
Mutation Taster		=59/41	polymorphism

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: rs199641554; hg19: chr3-107435515; COSMIC: COSV105214851; COSMIC: COSV105214851;