12-92144169-C-A

Variant names:

• chr12-92144169-C-A
• rs768708869
• NM_001731.3:c.427G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001731.3(BTG1):​c.427G>T​(p.Val143Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BTG1 NM_001731.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54

Genes affected

BTG1 (HGNC:1130): (BTG anti-proliferation factor 1) This gene is a member of an anti-proliferative gene family that regulates cell growth and differentiation. Expression of this gene is highest in the G0/G1 phases of the cell cycle and downregulated when cells progressed through G1. The encoded protein interacts with several nuclear receptors, and functions as a coactivator of cell differentiation. This locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2183105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTG1	NM_001731.3	c.427G>T	p.Val143Leu	missense_variant	Exon 2 of 2	ENST00000256015.5	NP_001722.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTG1	ENST00000256015.5	c.427G>T	p.Val143Leu	missense_variant	Exon 2 of 2	1	NM_001731.3	ENSP00000256015.3
BTG1	ENST00000552315.1	n.453G>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
BTG1	ENST00000673901.1	n.331G>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251392 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

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 AF: 0.00000479 AC: 7 AN: 1461830 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.427G>T (p.V143L) alteration is located in exon 2 (coding exon 2) of the BTG1 gene. This alteration results from a G to T substitution at nucleotide position 427, causing the valine (V) at amino acid position 143 to be replaced by a leucine (L). 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	0.18
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.071	T;.
Eigen	Benign	0.021
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	D;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.17
Sift	Benign	0.17	T;T
Sift4G	Benign	0.78	T;.
Polyphen		0.0010	B;.
Vest4		0.10
MutPred		0.29		Gain of catalytic residue at T138 (P = 0.0068);.;
MVP		0.50
MPC		0.67
ClinPred		0.27	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.31

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: rs768708869; hg19: chr12-92537945;