11-67633004-A-C

Variant names:

• chr11-67633004-A-C
• rs201886785
• NM_005995.5:c.649T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005995.5(TBX10):​c.649T>G​(p.Ser217Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S217T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBX10 NM_005995.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005995.5. 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
	TBX10	NM_005995.5	MANE Select	c.649T>G	p.Ser217Ala	missense	Exon 5 of 8	NP_005986.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX10	ENST00000335385.4	TSL:1 MANE Select	c.649T>G	p.Ser217Ala	missense	Exon 5 of 8	ENSP00000335191.3	O75333

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.0066	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.068	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.38
Sift	Benign	0.055	T
Sift4G	Benign	0.084	T
Polyphen		0.73	P
Vest4		0.48
MutPred		0.74		Loss of disorder (P = 0.0798)
MVP		0.64
MPC		0.16
ClinPred		0.89	D
GERP RS		4.2
Varity_R		0.24
gMVP		0.38
Mutation Taster		=77/23	polymorphism

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: rs201886785; hg19: chr11-67400475;