rs2236017

Variant names:

• chr12-114394705-C-A
• rs2236017
• NM_181486.4:c.663+36G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-114394705-C-A
• chr12-114394705-C-G
• chr12-114394705-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181486.4(TBX5):​c.663+36G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,612,396 control chromosomes in the GnomAD database, including 308,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25471 hom., cov: 31)
  • Exomes 𝑓: 0.62 (283352 hom.)
• Consequence: TBX5 NM_181486.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: -0.956
• Publications: 14 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• 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 (BayesDel_noAF=-0.83).
• BP6: Variant 12-114394705-C-A is Benign according to our data. Variant chr12-114394705-C-A is described in ClinVar as Benign. ClinVar VariationId is 139592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.663+36G>T		intron_variant	Intron 6 of 8	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.663+36G>T		intron_variant	Intron 6 of 8		NP_000183.2
TBX5	NM_080717.4	c.513+36G>T		intron_variant	Intron 5 of 7		NP_542448.1
TBX5	XM_017019912.2	c.711+36G>T		intron_variant	Intron 6 of 8		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.663+36G>T		intron_variant	Intron 6 of 8	1	NM_181486.4	ENSP00000384152.3

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86344 AN: 151822 Hom.: 25451 Cov.: 31

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.619

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.589

GnomAD2 exomes AF: 0.619 AC: 155374 AN: 251088 AF XY: 0.622

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.619

Gnomad NFE exome AF: 0.628

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.619 AC: 904338 AN: 1460456 Hom.: 283352 Cov.: 39 AF XY: 0.620 AC XY: 450819 AN XY: 726584

African (AFR) AF: 0.415 AC: 13863 AN: 33444

American (AMR) AF: 0.782 AC: 34954 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.620 AC: 16204 AN: 26116

East Asian (EAS) AF: 0.364 AC: 14427 AN: 39684

South Asian (SAS) AF: 0.670 AC: 57725 AN: 86212

European-Finnish (FIN) AF: 0.611 AC: 32525 AN: 53232

Middle Eastern (MID) AF: 0.594 AC: 3413 AN: 5748

European-Non Finnish (NFE) AF: 0.626 AC: 695427 AN: 1110978

Other (OTH) AF: 0.593 AC: 35800 AN: 60330

GnomAD4 genome AF: 0.569 AC: 86413 AN: 151940 Hom.: 25471 Cov.: 31 AF XY: 0.573 AC XY: 42549 AN XY: 74238

African (AFR) AF: 0.424 AC: 17552 AN: 41406

American (AMR) AF: 0.715 AC: 10927 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2138 AN: 3462

East Asian (EAS) AF: 0.347 AC: 1786 AN: 5140

South Asian (SAS) AF: 0.674 AC: 3239 AN: 4806

European-Finnish (FIN) AF: 0.619 AC: 6537 AN: 10568

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42409 AN: 67964

Other (OTH) AF: 0.589 AC: 1245 AN: 2114

Alfa AF: 0.552 Hom.: 7981

Bravo AF: 0.566

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Molecular Genetics and Enzymology, National Research Centre

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Holt-Oram syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.18
DANN	Benign	0.60
PhyloP100		-0.96
Mutation Taster		=100/0	polymorphism (auto)

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: rs2236017; hg19: chr12-114832510; COSMIC: COSV59860963; COSMIC: COSV59860963;