1-118884844-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330677.2(TBX15):c.1697T>G(p.Met566Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,614,162 control chromosomes in the GnomAD database, including 2,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (153 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2017 hom.)
• Consequence: TBX15 NM_001330677.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.60

Genes affected

TBX15 (HGNC:11594): (T-box transcription factor 15) This gene belongs to the T-box family of genes, which encode a phylogenetically conserved family of transcription factors that regulate a variety of developmental processes. All these genes contain a common T-box DNA-binding domain. Mutations in this gene are associated with Cousin syndrome.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022727847).
• BP6: Variant 1-118884844-A-C is Benign according to our data. Variant chr1-118884844-A-C is described in ClinVar as [Benign]. Clinvar id is 594474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-118884844-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX15	NM_001330677.2	c.1697T>G	p.Met566Arg	missense_variant	8/8	ENST00000369429.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX15	ENST00000369429.5	c.1697T>G	p.Met566Arg	missense_variant	8/8	5	NM_001330677.2	P1
TBX15	ENST00000207157.7	c.1379T>G	p.Met460Arg	missense_variant	8/8	1
TBX15	ENST00000449873.5	c.881T>G	p.Met294Arg	missense_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5202 AN: 152180 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.00813

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0975

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0478

GnomAD3 exomes AF: 0.0446 AC: 11198 AN: 250914 Hom.: 392 AF XY: 0.0497 AC XY: 6737 AN XY: 135586

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.0321

Gnomad ASJ exome AF: 0.0955

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0986

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0464

Gnomad OTH exome AF: 0.0521

GnomAD4 exome AF: 0.0468 AC: 68487 AN: 1461864 Hom.: 2017 Cov.: 33 AF XY: 0.0489 AC XY: 35596 AN XY: 727234

Gnomad4 AFR exome AF: 0.00630

Gnomad4 AMR exome AF: 0.0332

Gnomad4 ASJ exome AF: 0.0936

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0996

Gnomad4 FIN exome AF: 0.0201

Gnomad4 NFE exome AF: 0.0462

Gnomad4 OTH exome AF: 0.0484

GnomAD4 genome AF: 0.0341 AC: 5198 AN: 152298 Hom.: 153 Cov.: 32 AF XY: 0.0343 AC XY: 2555 AN XY: 74468

Gnomad4 AFR AF: 0.00811

Gnomad4 AMR AF: 0.0411

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0967

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0449

Gnomad4 OTH AF: 0.0473

Alfa AF: 0.0438 Hom.: 256

Bravo AF: 0.0333

TwinsUK AF: 0.0402 AC: 149

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0478 AC: 411

ExAC AF: 0.0441 AC: 5355

Asia WGS AF: 0.0330 AC: 114 AN: 3478

EpiCase AF: 0.0545

EpiControl AF: 0.0543

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2019	This variant is associated with the following publications: (PMID: 28146470) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 20, 2017

- -

Pelviscapular dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Uncertain	0.10	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N;D;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.019	D;T;D
Polyphen		0.98	.;.;D
Vest4		0.41
MPC		0.52
ClinPred		0.049	T
GERP RS		5.3
Varity_R		0.79
gMVP		0.74

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: rs61730011; hg19: chr1-119427467; COSMIC: COSV52874432;