chr1-118884871-T-C

Variant names:

• chr1-118884871-T-C
• rs1571141808
• NM_001330677.2:c.1670A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001330677.2(TBX15):​c.1670A>G​(p.Tyr557Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y557F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX15 NM_001330677.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55
• Publications: 0 publications found

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]

TBX15 Gene-Disease associations (from GenCC):

• pelviscapular dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31831303).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330677.2. 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
	TBX15	NM_001330677.2	MANE Select	c.1670A>G	p.Tyr557Cys	missense	Exon 8 of 8	NP_001317606.1	Q96SF7-1
	TBX15	NM_152380.3		c.1352A>G	p.Tyr451Cys	missense	Exon 8 of 8	NP_689593.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX15	ENST00000369429.5	TSL:5 MANE Select	c.1670A>G	p.Tyr557Cys	missense	Exon 8 of 8	ENSP00000358437.3	Q96SF7-1
	TBX15	ENST00000207157.7	TSL:1	c.1352A>G	p.Tyr451Cys	missense	Exon 8 of 8	ENSP00000207157.3	Q96SF7-2
	TBX15	ENST00000449873.5	TSL:5	c.854A>G	p.Tyr285Cys	missense	Exon 4 of 4	ENSP00000398625.1	Q5JT55

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	2.0	M
PhyloP100		4.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.045	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.11		Loss of phosphorylation at Y557 (P = 0.0284)
MVP		0.73
MPC		1.1
ClinPred		0.83	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.47
Mutation Taster		=34/66	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: rs1571141808; hg19: chr1-119427494; COSMIC: COSV52875457;