NM_001330677.2:c.466C>A

Variant names:

• chr1-118926565-G-T
• rs10494217
• NM_001330677.2:c.466C>A

Variant summary

Our verdict is Benign. The variant received -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 (★★).

• 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
• Publications: 47 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, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330677.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX15	NM_001330677.2	MANE Select	c.466C>A	p.His156Asn	missense	Exon 3 of 8	NP_001317606.1	Q96SF7-1
	TBX15	NM_152380.3		c.148C>A	p.His50Asn	missense	Exon 3 of 8	NP_689593.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX15	ENST00000369429.5	TSL:5 MANE Select	c.466C>A	p.His156Asn	missense	Exon 3 of 8	ENSP00000358437.3	Q96SF7-1
	TBX15	ENST00000207157.7	TSL:1	c.148C>A	p.His50Asn	missense	Exon 3 of 8	ENSP00000207157.3	Q96SF7-2

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

GnomAD2 exomes AF: 0.144 AC: 36201 AN: 250946 AF XY: 0.146

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 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

African (AFR) AF: 0.0234 AC: 782 AN: 33468

American (AMR) AF: 0.0865 AC: 3866 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 3083 AN: 26122

East Asian (EAS) AF: 0.0623 AC: 2473 AN: 39670

South Asian (SAS) AF: 0.0951 AC: 8201 AN: 86220

European-Finnish (FIN) AF: 0.276 AC: 14739 AN: 53366

Middle Eastern (MID) AF: 0.0760 AC: 438 AN: 5762

European-Non Finnish (NFE) AF: 0.180 AC: 199364 AN: 1110334

Other (OTH) AF: 0.148 AC: 8954 AN: 60308

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

African (AFR) AF: 0.0288 AC: 1197 AN: 41544

American (AMR) AF: 0.104 AC: 1596 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3470

East Asian (EAS) AF: 0.0709 AC: 368 AN: 5190

South Asian (SAS) AF: 0.0977 AC: 472 AN: 4830

European-Finnish (FIN) AF: 0.280 AC: 2957 AN: 10572

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12174 AN: 67998

Other (OTH) AF: 0.121 AC: 257 AN: 2116

Alfa AF: 0.154 Hom.: 7092

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Pelviscapular dysplasia (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.35	N
PhyloP100		10
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.35
Sift	Benign	0.47	T
Sift4G	Benign	0.50	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
Mutation Taster		=19/81	polymorphism (auto)

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