6-32041892-C-T

Variant names:

• chr6-32041892-C-T
• rs544604053
• NM_001365276.2:c.12512G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001365276.2(TNXB):​c.12512G>A​(p.Arg4171His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (8 hom., cov: 12)
  • Exomes 𝑓: 0.00066 (13 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.230
• Publications: 0 publications found

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]

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A member 2) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYP21A2 Gene-Disease associations (from GenCC):

• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009919435).
• BP6: Variant 6-32041892-C-T is Benign according to our data. Variant chr6-32041892-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224352.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00406 (397/97678) while in subpopulation AFR AF = 0.014 (357/25564). AF 95% confidence interval is 0.0128. There are 8 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 12. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. 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
	TNXB	NM_001365276.2	MANE Select	c.12512G>A	p.Arg4171His	missense	Exon 43 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.13253G>A	p.Arg4418His	missense	Exon 44 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.12506G>A	p.Arg4169His	missense	Exon 43 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.12512G>A	p.Arg4171His	missense	Exon 43 of 44	ENSP00000496448.1
	TNXB	ENST00000451343.4	TSL:1	c.1799G>A	p.Arg600His	missense	Exon 12 of 13	ENSP00000407685.1
	TNXB	ENST00000490077.5	TSL:1	n.2339G>A		non_coding_transcript_exon	Exon 13 of 14

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 396 AN: 97580 Hom.: 8 Cov.: 12

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

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: 0.000109

Gnomad OTH AF: 0.000790

GnomAD2 exomes AF: 0.00124 AC: 140 AN: 113134 AF XY: 0.00105

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000985

Gnomad OTH exome AF: 0.000836

GnomAD4 exome AF: 0.000660 AC: 394 AN: 596974 Hom.: 13 Cov.: 6 AF XY: 0.000515 AC XY: 162 AN XY: 314618

African (AFR) AF: 0.0145 AC: 251 AN: 17330

American (AMR) AF: 0.00223 AC: 74 AN: 33172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18838

East Asian (EAS) AF: 0.00 AC: 0 AN: 31970

South Asian (SAS) AF: 0.0000160 AC: 1 AN: 62692

European-Finnish (FIN) AF: 0.0000263 AC: 1 AN: 38044

Middle Eastern (MID) AF: 0.000782 AC: 2 AN: 2556

European-Non Finnish (NFE) AF: 0.0000416 AC: 15 AN: 360598

Other (OTH) AF: 0.00157 AC: 50 AN: 31774

GnomAD4 genome AF: 0.00406 AC: 397 AN: 97678 Hom.: 8 Cov.: 12 AF XY: 0.00412 AC XY: 187 AN XY: 45362

African (AFR) AF: 0.0140 AC: 357 AN: 25564

American (AMR) AF: 0.00366 AC: 34 AN: 9286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2396

East Asian (EAS) AF: 0.00 AC: 0 AN: 3832

South Asian (SAS) AF: 0.00 AC: 0 AN: 2722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.000109 AC: 5 AN: 46024

Other (OTH) AF: 0.000780 AC: 1 AN: 1282

Alfa AF: 0.00207 Hom.: 1

ExAC AF: 0.000487 AC: 13

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	TNXB-related disorder (1)
-	1	-	Vesicoureteral reflux 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.035
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.033	N
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.67	T
PhyloP100		0.23
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.29
Sift	Benign	0.25	T
Sift4G	Uncertain	0.0030	D
Vest4		0.17
MVP		0.51
MPC		3.4
ClinPred		0.026	T
GERP RS		3.8
Varity_R		0.19
gMVP		0.35
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs544604053; hg19: chr6-32009669;