21-17604214-G-A

Variant names:

• chr21-17604214-G-A
• rs770143908
• ENST00000339775.10:c.374C>T

Variant summary

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

The NM_001130914.2(BTG3):​c.374C>T​(p.Pro125Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 870,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict 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: 0.000093 (0 hom.)
• Consequence: BTG3 NM_001130914.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.970

Genes affected

BTG3 (HGNC:1132): (BTG anti-proliferation factor 3) The protein encoded by this gene is a member of the BTG/Tob family. This family has structurally related proteins that appear to have antiproliferative properties. This encoded protein might play a role in neurogenesis in the central nervous system. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

CXADR (HGNC:2559): (CXADR Ig-like cell adhesion molecule) The protein encoded by this gene is a type I membrane receptor for group B coxsackieviruses and subgroup C adenoviruses. Several transcript variants encoding different isoforms have been found for this gene. Pseudogenes of this gene are found on chromosomes 15, 18, and 21. [provided by RefSeq, May 2011]

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=0.014694244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTG3	NM_006806.5	c.311+646C>T		intron_variant	Intron 3 of 4	ENST00000348354.7	NP_006797.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTG3	ENST00000339775.10	c.374C>T	p.Pro125Leu	missense_variant	Exon 4 of 6	1		ENSP00000344609.6
BTG3	ENST00000348354.7	c.311+646C>T		intron_variant	Intron 3 of 4	1	NM_006806.5	ENSP00000284879.8
BTG3	ENST00000496601.1	n.274+646C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 11 AN: 74746 Hom.: 0 AF XY: 0.000124 AC XY: 5 AN XY: 40192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000427

Gnomad ASJ exome AF: 0.00154

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000932 AC: 67 AN: 718918 Hom.: 0 Cov.: 10 AF XY: 0.0000770 AC XY: 28 AN XY: 363836

Gnomad4 AFR exome AF: 0.0000844

Gnomad4 AMR exome AF: 0.000486

Gnomad4 ASJ exome AF: 0.00212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000179

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000598

Gnomad4 OTH exome AF: 0.000192

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74292

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000212

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000128 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374C>T (p.P125L) alteration is located in exon 4 (coding exon 3) of the BTG3 gene. This alteration results from a C to T substitution at nucleotide position 374, causing the proline (P) at amino acid position 125 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
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.2
DANN	Benign	0.34
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.017
Sift	Benign	1.0	T
Sift4G	Benign	0.069	T
Polyphen		0.062	B
Vest4		0.17
MutPred		0.45		Gain of sheet (P = 0.0149);
MVP		0.043
MPC		2.3
ClinPred		0.085	T
GERP RS		-0.54
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs770143908; hg19: chr21-18976532; COSMIC: COSV60286787; COSMIC: COSV60286787;