rs10494217

Positions:

• chr1-118926565-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330677.2(TBX15):​c.466C>A​(p.His156Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,612,184 control chromosomes in the GnomAD database, including 23,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1784 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21931 hom.)
• Consequence: TBX15 NM_001330677.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017850101).
• BP6: Variant 1-118926565-G-T is Benign according to our data. Variant chr1-118926565-G-T is described in ClinVar as [Benign]. Clinvar id is 1240908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX15	NM_001330677.2	c.466C>A	p.His156Asn	missense_variant	3/8	ENST00000369429.5	NP_001317606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX15	ENST00000369429.5	c.466C>A	p.His156Asn	missense_variant	3/8	5	NM_001330677.2	ENSP00000358437.3
TBX15	ENST00000207157.7	c.148C>A	p.His50Asn	missense_variant	3/8	1		ENSP00000207157.3

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19557 AN: 152108 Hom.: 1782 Cov.: 33

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0704

Gnomad SAS AF: 0.0978

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.122

GnomAD3 exomes AF: 0.144 AC: 36201 AN: 250946 Hom.: 3229 AF XY: 0.146 AC XY: 19743 AN XY: 135630

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.0855

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.0729

Gnomad SAS exome AF: 0.0944

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.166 AC: 241900 AN: 1459958 Hom.: 21931 Cov.: 32 AF XY: 0.164 AC XY: 119119 AN XY: 726340

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.0865

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.0623

Gnomad4 SAS exome AF: 0.0951

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.180

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.128 AC: 19558 AN: 152226 Hom.: 1784 Cov.: 33 AF XY: 0.132 AC XY: 9828 AN XY: 74414

Gnomad4 AFR AF: 0.0288

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.0709

Gnomad4 SAS AF: 0.0977

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.121

Alfa AF: 0.163 Hom.: 5315

Bravo AF: 0.112

TwinsUK AF: 0.172 AC: 638

ALSPAC AF: 0.175 AC: 675

ESP6500AA AF: 0.0343 AC: 151

ESP6500EA AF: 0.181 AC: 1560

ExAC AF: 0.144 AC: 17519

Asia WGS AF: 0.100 AC: 346 AN: 3478

EpiCase AF: 0.161

EpiControl AF: 0.165

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Pelviscapular dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.26	.;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.35	.;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.47	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.12	.;B
Vest4		0.31
MPC		0.35
ClinPred		0.054	T
GERP RS		6.1
Varity_R		0.29
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs10494217; hg19: chr1-119469188; COSMIC: COSV52871319;