chr6-32097417-G-A

Variant names:

• chr6-32097417-G-A
• rs1780476790
• NM_001365276.2:c.436C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001365276.2(TNXB):​c.436C>T​(p.His146Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,286 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79

Genes affected

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.436C>T	p.His146Tyr	missense_variant	Exon 3 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.436C>T	p.His146Tyr	missense_variant	Exon 3 of 45		NP_001415264.1
TNXB	NM_019105.8	c.436C>T	p.His146Tyr	missense_variant	Exon 3 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.436C>T	p.His146Tyr	missense_variant	Exon 3 of 44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453286 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 722616

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.37	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.6	.;.;D;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.026	.;.;D;.;D
Sift4G	Pathogenic	0.0010	.;.;D;D;D
Vest4		0.37, 0.51
MutPred		0.59		Loss of disorder (P = 0.0555);Loss of disorder (P = 0.0555);Loss of disorder (P = 0.0555);Loss of disorder (P = 0.0555);Loss of disorder (P = 0.0555);
MVP		0.31
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1780476790; hg19: chr6-32065194;