chr1-118884605-GAA-G

Variant names:

• chr1-118884605-GAA-G
• rs536044359
• NM_001330677.2:c.*125_*126delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001330677.2(TBX15):​c.*125_*126delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 759,136 control chromosomes in the GnomAD database, including 23 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (23 hom., cov: 27)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: TBX15 NM_001330677.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.818
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0167 (1348/80768) while in subpopulation AFR AF = 0.0469 (1276/27214). AF 95% confidence interval is 0.0447. There are 23 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX15	NM_001330677.2	c.*125_*126delTT		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.*125_*126delTT		3_prime_UTR_variant	Exon 8 of 8	5	NM_001330677.2	ENSP00000358437.3
TBX15	ENST00000207157.7	c.*125_*126delTT		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000207157.3
TBX15	ENST00000449873.5	c.*125_*126delTT		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000398625.1

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 1347 AN: 80748 Hom.: 23 Cov.: 27

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00734

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000461

Gnomad SAS AF: 0.000997

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000251

Gnomad OTH AF: 0.00914

GnomAD4 exome AF: 0.0155 AC: 10482 AN: 678368 Hom.: 0 AF XY: 0.0153 AC XY: 5303 AN XY: 347194

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

African (AFR) AF: 0.0466 AC: 746 AN: 16020

American (AMR) AF: 0.0163 AC: 303 AN: 18558

Ashkenazi Jewish (ASJ) AF: 0.0186 AC: 268 AN: 14444

East Asian (EAS) AF: 0.0181 AC: 527 AN: 29092

South Asian (SAS) AF: 0.00993 AC: 478 AN: 48152

European-Finnish (FIN) AF: 0.0151 AC: 427 AN: 28322

Middle Eastern (MID) AF: 0.0175 AC: 40 AN: 2292

European-Non Finnish (NFE) AF: 0.0145 AC: 7088 AN: 489266

Other (OTH) AF: 0.0188 AC: 605 AN: 32222

⚠️ 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: 0.0167 AC: 1348 AN: 80768 Hom.: 23 Cov.: 27 AF XY: 0.0171 AC XY: 647 AN XY: 37856

African (AFR) AF: 0.0469 AC: 1276 AN: 27214

American (AMR) AF: 0.00733 AC: 50 AN: 6822

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

East Asian (EAS) AF: 0.000461 AC: 1 AN: 2170

South Asian (SAS) AF: 0.000993 AC: 2 AN: 2014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 114

European-Non Finnish (NFE) AF: 0.000251 AC: 9 AN: 35826

Other (OTH) AF: 0.00916 AC: 10 AN: 1092

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism

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: rs536044359; hg19: chr1-119427228;