1-118884605-GAAAAAAAAAA-GAAAAAAAAAAAAA

Variant names:

• chr1-118884605-G-GAAA
• rs536044359
• NM_001330677.2:c.*124_*126dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001330677.2(TBX15):​c.*124_*126dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 758,864 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 27)
  • Exomes 𝑓: 0.011 (1 hom.)
• Consequence: TBX15 NM_001330677.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.512
• 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.0118) population. However there is too low homozygotes in high coverage region: (expected more than 19, got 1).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX15	NM_001330677.2	c.*124_*126dupTTT		3_prime_UTR_variant	Exon 8 of 8	ENST00000369429.5	NP_001317606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX15	ENST00000369429.5	c.*124_*126dupTTT		3_prime_UTR_variant	Exon 8 of 8	5	NM_001330677.2	ENSP00000358437.3
TBX15	ENST00000207157.7	c.*124_*126dupTTT		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000207157.3
TBX15	ENST00000449873.5	c.*124_*126dupTTT		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000398625.1

Frequencies

GnomAD3 genomes AF: 0.000372 AC: 30 AN: 80740 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000441

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000630

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000586

Gnomad OTH AF: 0.000914

GnomAD4 exome AF: 0.0113 AC: 7645 AN: 678124 Hom.: 1 Cov.: 6 AF XY: 0.0112 AC XY: 3874 AN XY: 347036

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0106 AC: 170 AN: 16110

American (AMR) AF: 0.00709 AC: 131 AN: 18484

Ashkenazi Jewish (ASJ) AF: 0.00788 AC: 114 AN: 14470

East Asian (EAS) AF: 0.00389 AC: 114 AN: 29272

South Asian (SAS) AF: 0.00885 AC: 423 AN: 47810

European-Finnish (FIN) AF: 0.0143 AC: 405 AN: 28290

Middle Eastern (MID) AF: 0.00785 AC: 18 AN: 2292

European-Non Finnish (NFE) AF: 0.0121 AC: 5903 AN: 489186

Other (OTH) AF: 0.0114 AC: 367 AN: 32210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000372 AC: 30 AN: 80740 Hom.: 0 Cov.: 27 AF XY: 0.000344 AC XY: 13 AN XY: 37828

African (AFR) AF: 0.000110 AC: 3 AN: 27198

American (AMR) AF: 0.000441 AC: 3 AN: 6808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1932

East Asian (EAS) AF: 0.00 AC: 0 AN: 2172

South Asian (SAS) AF: 0.00 AC: 0 AN: 2006

European-Finnish (FIN) AF: 0.000630 AC: 2 AN: 3174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 120

European-Non Finnish (NFE) AF: 0.000586 AC: 21 AN: 35828

Other (OTH) AF: 0.000914 AC: 1 AN: 1094

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs536044359; hg19: chr1-119427228;