chr1-118884605-G-GAA

Variant names:

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

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.*125_*126dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0659 in 734,556 control chromosomes in the GnomAD database, including 50 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (45 hom., cov: 27)
  • Exomes 𝑓: 0.070 (5 hom.)
• Consequence: TBX15 NM_001330677.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-118884605-G-GAA is Benign according to our data. Variant chr1-118884605-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 1253783.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0339 (2736/80712) while in subpopulation NFE AF = 0.05 (1789/35782). AF 95% confidence interval is 0.0481. There are 45 homozygotes in GnomAd4. There are 1310 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 2734 AN: 80692 Hom.: 45 Cov.: 27

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.0172

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.0140

Gnomad EAS AF: 0.000921

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.0250

Gnomad NFE AF: 0.0500

Gnomad OTH AF: 0.0265

GnomAD4 exome AF: 0.0699 AC: 45685 AN: 653844 Hom.: 5 Cov.: 6 AF XY: 0.0701 AC XY: 23407 AN XY: 334040

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

African (AFR) AF: 0.0678 AC: 1057 AN: 15580

American (AMR) AF: 0.0669 AC: 1171 AN: 17510

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 901 AN: 13852

East Asian (EAS) AF: 0.0505 AC: 1405 AN: 27816

South Asian (SAS) AF: 0.0761 AC: 3423 AN: 44990

European-Finnish (FIN) AF: 0.0725 AC: 1976 AN: 27248

Middle Eastern (MID) AF: 0.0683 AC: 152 AN: 2226

European-Non Finnish (NFE) AF: 0.0707 AC: 33470 AN: 473518

Other (OTH) AF: 0.0685 AC: 2130 AN: 31104

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0339 AC: 2736 AN: 80712 Hom.: 45 Cov.: 27 AF XY: 0.0346 AC XY: 1310 AN XY: 37838

African (AFR) AF: 0.0137 AC: 372 AN: 27210

American (AMR) AF: 0.0280 AC: 191 AN: 6820

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 27 AN: 1932

East Asian (EAS) AF: 0.000921 AC: 2 AN: 2172

South Asian (SAS) AF: 0.0114 AC: 23 AN: 2010

European-Finnish (FIN) AF: 0.0924 AC: 293 AN: 3172

Middle Eastern (MID) AF: 0.0263 AC: 3 AN: 114

European-Non Finnish (NFE) AF: 0.0500 AC: 1789 AN: 35782

Other (OTH) AF: 0.0266 AC: 29 AN: 1092

Alfa AF: 0.00700 Hom.: 6

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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; COSMIC: COSV52873172;