1-118884605-GAAAA-G

Variant names:

• chr1-118884605-GAAAA-G
• rs536044359
• NM_001330677.2:c.*123_*126delTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001330677.2(TBX15):​c.*123_*126delTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 767,070 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0082 (5 hom., cov: 27)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: TBX15 NM_001330677.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 1-118884605-GAAAA-G is Benign according to our data. Variant chr1-118884605-GAAAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 1214267.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00818 (661/80766) while in subpopulation AFR AF = 0.023 (625/27214). AF 95% confidence interval is 0.0215. There are 5 homozygotes in GnomAd4. There are 310 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX15	NM_001330677.2	c.*123_*126delTTTT		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.*123_*126delTTTT		3_prime_UTR_variant	Exon 8 of 8	5	NM_001330677.2	ENSP00000358437.3
TBX15	ENST00000207157.7	c.*123_*126delTTTT		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000207157.3
TBX15	ENST00000449873.5	c.*123_*126delTTTT		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000398625.1

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 662 AN: 80746 Hom.: 5 Cov.: 27

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00155

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000167

Gnomad OTH AF: 0.00548

GnomAD4 exome AF: 0.00184 AC: 1262 AN: 686304 Hom.: 0 AF XY: 0.00169 AC XY: 592 AN XY: 351298

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

African (AFR) AF: 0.0179 AC: 291 AN: 16292

American (AMR) AF: 0.00197 AC: 37 AN: 18770

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 37 AN: 14596

East Asian (EAS) AF: 0.00129 AC: 38 AN: 29528

South Asian (SAS) AF: 0.000718 AC: 35 AN: 48764

European-Finnish (FIN) AF: 0.00129 AC: 37 AN: 28690

Middle Eastern (MID) AF: 0.00172 AC: 4 AN: 2328

European-Non Finnish (NFE) AF: 0.00143 AC: 706 AN: 494698

Other (OTH) AF: 0.00236 AC: 77 AN: 32638

⚠️ 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: 0.00818 AC: 661 AN: 80766 Hom.: 5 Cov.: 27 AF XY: 0.00819 AC XY: 310 AN XY: 37852

African (AFR) AF: 0.0230 AC: 625 AN: 27214

American (AMR) AF: 0.00308 AC: 21 AN: 6820

Ashkenazi Jewish (ASJ) AF: 0.00155 AC: 3 AN: 1932

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

South Asian (SAS) AF: 0.00 AC: 0 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: 0.000167 AC: 6 AN: 35824

Other (OTH) AF: 0.00549 AC: 6 AN: 1092

Alfa AF: 0.00 Hom.: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 19, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;