17-61456561-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001321120.2(TBX4):c.71C>T(p.Ala24Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,546,928 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (5 hom.)
• Consequence: TBX4 NM_001321120.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

Genes affected

TBX4 (HGNC:11603): (T-box transcription factor 4) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity. [provided by RefSeq, Jul 2008]

LOC124904042 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004690945).
• BP6: Variant 17-61456561-C-T is Benign according to our data. Variant chr17-61456561-C-T is described in ClinVar as [Benign]. Clinvar id is 2415719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000118 (18/152186) while in subpopulation SAS AF= 0.00352 (17/4826). AF 95% confidence interval is 0.00224. There are 1 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.71C>T	p.Ala24Val	missense_variant	2/9	ENST00000644296.1
LOC124904042	XR_007065872.1	n.2142G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.71C>T	p.Ala24Val	missense_variant	2/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.71C>T	p.Ala24Val	missense_variant	1/8	1		P4
TBX4	ENST00000642491.1	c.71C>T	p.Ala24Val	missense_variant	1/8			A1
TBX4	ENST00000589003.5	c.-125-63C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152074 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000550 AC: 80 AN: 145498 Hom.: 4 AF XY: 0.000677 AC XY: 53 AN XY: 78266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000934

Gnomad OTH exome AF: 0.000238

GnomAD4 exome AF: 0.000232 AC: 323 AN: 1394742 Hom.: 5 Cov.: 32 AF XY: 0.000323 AC XY: 222 AN XY: 688044

Gnomad4 AFR exome AF: 0.0000319

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00310

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000622

Gnomad4 OTH exome AF: 0.000156

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152186 Hom.: 1 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74388

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000468 AC: 42

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 21, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.43	N
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.0047	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N;N;N;N
MutationTaster	Benign	0.93	N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.64	N;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.16	T;.;T;.
Sift4G	Benign	0.31	T;.;T;.
Polyphen		0.0010	.;.;B;.
Vest4		0.17
MutPred		0.24		Gain of sheet (P = 0.0507);Gain of sheet (P = 0.0507);Gain of sheet (P = 0.0507);Gain of sheet (P = 0.0507);
MVP		0.62
MPC		0.40
ClinPred		0.025	T
GERP RS		0.87
Varity_R		0.084
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs573485618; hg19: chr17-59533922;