11-67631755-G-T

Variant names:

• chr11-67631755-G-T
• rs781132994
• NM_005995.5:c.1008C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005995.5(TBX10):​c.1008C>A​(p.Ser336Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,608,468 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TBX10 NM_005995.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0360
• 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051754504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX10	NM_005995.5	c.1008C>A	p.Ser336Arg	missense_variant	Exon 8 of 8	ENST00000335385.4	NP_005986.2
TBX10	XM_047426879.1	c.1881C>A	p.Ser627Arg	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	c.1008C>A	p.Ser336Arg	missense_variant	Exon 8 of 8	1	NM_005995.5	ENSP00000335191.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000254 AC: 6 AN: 236102 AF XY: 0.0000156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1456324 Hom.: 0 Cov.: 32 AF XY: 0.0000111 AC XY: 8 AN XY: 723792

African (AFR) AF: 0.0000299 AC: 1 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 43818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.000278 AC: 11 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 84884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109956

Other (OTH) AF: 0.0000166 AC: 1 AN: 60146

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1008C>A (p.S336R) alteration is located in exon 8 (coding exon 8) of the TBX10 gene. This alteration results from a C to A substitution at nucleotide position 1008, causing the serine (S) at amino acid position 336 to be replaced by an arginine (R). 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	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.1
DANN	Benign	0.87
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.036
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.077
Sift	Benign	0.048	D
Sift4G	Benign	0.24	T
Polyphen		0.26	B
Vest4		0.12
MutPred		0.27		Loss of glycosylation at S336 (P = 0.0085);
MVP		0.30
MPC		0.051
ClinPred		0.032	T
GERP RS		2.1
Varity_R		0.066
gMVP		0.26
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs781132994; hg19: chr11-67399226; COSMIC: COSV56875328; COSMIC: COSV56875328;