rs115178276

Variant names:

• chr12-114366311-C-T
• rs115178276
• NM_181486.4:c.836G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-114366311-C-T
• chr12-114366311-C-A
• chr12-114366311-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181486.4(TBX5):​c.836G>A​(p.Arg279Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000165 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: TBX5 NM_181486.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.64
• Publications: 2 publications found

Genes affected

TBX5 (HGNC:11604): (T-box transcription factor 5) 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 closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

TBX5 Gene-Disease associations (from GenCC):

• Holt-Oram syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia, Orphanet
• heart conduction disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066298842).
• BP6: Variant 12-114366311-C-T is Benign according to our data. Variant chr12-114366311-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 264163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000835 (127/152158) while in subpopulation AFR AF = 0.00284 (118/41522). AF 95% confidence interval is 0.00243. There are 0 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 127 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181486.4. 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
	TBX5	NM_181486.4	MANE Select	c.836G>A	p.Arg279Gln	missense	Exon 8 of 9	NP_852259.1	Q99593-1
	TBX5	NM_000192.3		c.836G>A	p.Arg279Gln	missense	Exon 8 of 9	NP_000183.2	Q99593-1
	TBX5	NM_080717.4		c.686G>A	p.Arg229Gln	missense	Exon 7 of 8	NP_542448.1	Q99593-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX5	ENST00000405440.7	TSL:1 MANE Select	c.836G>A	p.Arg279Gln	missense	Exon 8 of 9	ENSP00000384152.3	Q99593-1
	TBX5	ENST00000310346.8	TSL:1	c.836G>A	p.Arg279Gln	missense	Exon 8 of 9	ENSP00000309913.4	Q99593-1
	TBX5	ENST00000349716.9	TSL:1	c.686G>A	p.Arg229Gln	missense	Exon 7 of 8	ENSP00000337723.5	Q99593-3

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 251400 AF XY: 0.000140

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000935 AC XY: 68 AN XY: 727242

African (AFR) AF: 0.00293 AC: 98 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

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

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112002

Other (OTH) AF: 0.000298 AC: 18 AN: 60394

GnomAD4 genome AF: 0.000835 AC: 127 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000941 AC XY: 70 AN XY: 74384

African (AFR) AF: 0.00284 AC: 118 AN: 41522

American (AMR) AF: 0.000327 AC: 5 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.000436 Hom.: 0

Bravo AF: 0.000929

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Aortic valve disease 2 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	TBX5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.95	L
PhyloP100		5.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.19
Sift	Benign	0.37	T
Sift4G	Benign	0.64	T
Polyphen		0.026	B
Vest4		0.26
MVP		0.51
MPC		0.16
ClinPred		0.030	T
GERP RS		4.7
Varity_R		0.057
gMVP		0.24
Mutation Taster		=66/34	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: rs115178276; hg19: chr12-114804116; COSMIC: COSV100091335;