Genetic Variant TBX10:p.Asn292Lys (chr11-67631887-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005995.5(TBX10):c.876C>G(p.Asn292Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,415,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TBX10
NM_005995.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00900

Publications

1 publications found

Variant links:

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]

TBX10 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06382376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX10	NM_005995.5 link	c.876C>G	p.Asn292Lys	missense_variant	Exon 8 of 8	ENST00000335385.4	NP_005986.2	O75333
TBX10	XM_047426879.1 link	c.1749C>G	p.Asn583Lys	missense_variant	Exon 11 of 11		XP_047282835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX10	ENST00000335385.4 link	c.876C>G	p.Asn292Lys	missense_variant	Exon 8 of 8	1	NM_005995.5	ENSP00000335191.3		O75333

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000115

AC:

AN:

173708

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000794

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1415860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33070

American (AMR)

AF:

0.0000552

AC:

AN:

36264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25256

East Asian (EAS)

AF:

0.00

AC:

AN:

38316

South Asian (SAS)

AF:

0.00

AC:

AN:

80552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087688

Other (OTH)

AF:

0.00

AC:

AN:

58766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.24

CADD

Benign

4.9

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.058

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.35

M_CAP

Benign

0.052

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.69

PhyloP100

0.0090

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.93

REVEL

Benign

0.17

Sift

Benign

0.34

Sift4G

Benign

0.79

Polyphen

0.026

Vest4

0.097

MutPred

0.36

Gain of methylation at N292 (P = 0.0042);

MVP

0.44

MPC

0.052

ClinPred

0.073

GERP RS

1.2

Varity_R

0.060

gMVP

0.25

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over