rs199731693

Variant names:

• chr12-114385441-T-C
• rs199731693
• NM_181486.4:c.755+35A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_181486.4(TBX5):​c.755+35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,593,752 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: TBX5 NM_181486.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.12
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-114385441-T-C is Benign according to our data. Variant chr12-114385441-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 255493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000526 (758/1441620) while in subpopulation NFE AF = 0.000625 (684/1093568). AF 95% confidence interval is 0.000586. There are 1 homozygotes in GnomAdExome4. There are 371 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 74 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.755+35A>G		intron	N/A	NP_852259.1	Q99593-1
	TBX5	NM_000192.3		c.755+35A>G		intron	N/A	NP_000183.2	Q99593-1
	TBX5	NM_080717.4		c.605+35A>G		intron	N/A	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.755+35A>G		intron	N/A	ENSP00000384152.3	Q99593-1
	TBX5	ENST00000310346.8	TSL:1	c.755+35A>G		intron	N/A	ENSP00000309913.4	Q99593-1
	TBX5	ENST00000349716.9	TSL:1	c.605+35A>G		intron	N/A	ENSP00000337723.5	Q99593-3

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 152014 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000378 AC: 95 AN: 251080 AF XY: 0.000361

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000526 AC: 758 AN: 1441620 Hom.: 1 Cov.: 28 AF XY: 0.000516 AC XY: 371 AN XY: 718616

African (AFR) AF: 0.0000302 AC: 1 AN: 33058

American (AMR) AF: 0.000582 AC: 26 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000816 AC: 7 AN: 85830

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53382

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5722

European-Non Finnish (NFE) AF: 0.000625 AC: 684 AN: 1093568

Other (OTH) AF: 0.000519 AC: 31 AN: 59776

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152132 Hom.: 1 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74376

African (AFR) AF: 0.000193 AC: 8 AN: 41518

American (AMR) AF: 0.000918 AC: 14 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68000

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.000434

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.8
DANN	Benign	0.69
PhyloP100		-1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs199731693; hg19: chr12-114823246;