11-67632644-G-T

Variant names:

• chr11-67632644-G-T
• NM_005995.5:c.732C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005995.5(TBX10):​c.732C>A​(p.Asn244Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX10 NM_005995.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

Genes affected

TBX10 (HGNC:11593): (T-box transcription factor 10) This gene encodes a member of the T-box family of transcription factors. These transcription factors share a DNA-binding domain called the T-box, and play a role in several developmental processes including early embryonic cell fate and organogenesis. The encoded protein is a member of the T-box 1 subfamily. Mutations in this gene are thought to be a cause of isolated cleft lip with or without cleft palate. [provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX10	NM_005995.5	c.732C>A	p.Asn244Lys	missense_variant	Exon 6 of 8	ENST00000335385.4	NP_005986.2
TBX10	XM_047426879.1	c.1605C>A	p.Asn535Lys	missense_variant	Exon 9 of 11		XP_047282835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX10	ENST00000335385.4	c.732C>A	p.Asn244Lys	missense_variant	Exon 6 of 8	1	NM_005995.5	ENSP00000335191.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.732C>A (p.N244K) alteration is located in exon 6 (coding exon 6) of the TBX10 gene. This alteration results from a C to A substitution at nucleotide position 732, causing the asparagine (N) at amino acid position 244 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		1.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.89		Gain of catalytic residue at N244 (P = 0.012);
MVP		0.85
MPC		0.34
ClinPred		1.0	D
GERP RS		1.8
Varity_R		0.94
gMVP		0.92
Mutation Taster		=48/52	disease causing

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

hg19: chr11-67400115;