rs11755562

Variant names:

• chr6-32042103-G-A
• rs11755562
• NM_001365276.2:c.12378C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365276.2(TNXB):​c.12378C>T​(p.Asp4126Asp) variant causes a synonymous 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (0 hom., cov: 9)
  • Exomes 𝑓: 0.0084 (16 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.51
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-32042103-G-A is Benign according to our data. Variant chr6-32042103-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 261123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0084 (4220/502122) while in subpopulation EAS AF = 0.043 (1355/31478). AF 95% confidence interval is 0.0411. There are 16 homozygotes in GnomAdExome4. There are 2317 alleles in the male GnomAdExome4 subpopulation. Median coverage is 5. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 16 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.12378C>T	p.Asp4126Asp	synonymous	Exon 42 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.13119C>T	p.Asp4373Asp	synonymous	Exon 43 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.12372C>T	p.Asp4124Asp	synonymous	Exon 42 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.12378C>T	p.Asp4126Asp	synonymous	Exon 42 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000451343.4	TSL:1	c.1665C>T	p.Asp555Asp	synonymous	Exon 11 of 13	ENSP00000407685.1	P22105-2
	TNXB	ENST00000490077.5	TSL:1	n.2205C>T		non_coding_transcript_exon	Exon 12 of 14

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 418 AN: 69564 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00789

Gnomad ASJ AF: 0.0362

Gnomad EAS AF: 0.0122

Gnomad SAS AF: 0.0113

Gnomad FIN AF: 0.000265

Gnomad MID AF: 0.0202

Gnomad NFE AF: 0.00580

Gnomad OTH AF: 0.00820

GnomAD2 exomes AF: 0.00735 AC: 685 AN: 93208 AF XY: 0.00791

Gnomad AFR exome AF: 0.000838

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.0105

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00840 AC: 4220 AN: 502122 Hom.: 16 Cov.: 5 AF XY: 0.00873 AC XY: 2317 AN XY: 265334

African (AFR) AF: 0.00196 AC: 29 AN: 14768

American (AMR) AF: 0.00503 AC: 154 AN: 30608

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 459 AN: 15536

East Asian (EAS) AF: 0.0430 AC: 1355 AN: 31478

South Asian (SAS) AF: 0.0117 AC: 622 AN: 53206

European-Finnish (FIN) AF: 0.000913 AC: 28 AN: 30654

Middle Eastern (MID) AF: 0.0265 AC: 58 AN: 2192

European-Non Finnish (NFE) AF: 0.00443 AC: 1310 AN: 295654

Other (OTH) AF: 0.00731 AC: 205 AN: 28026

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00599 AC: 417 AN: 69612 Hom.: 0 Cov.: 9 AF XY: 0.00648 AC XY: 198 AN XY: 30552

African (AFR) AF: 0.00202 AC: 35 AN: 17352

American (AMR) AF: 0.00787 AC: 49 AN: 6226

Ashkenazi Jewish (ASJ) AF: 0.0362 AC: 63 AN: 1740

East Asian (EAS) AF: 0.0123 AC: 37 AN: 3012

South Asian (SAS) AF: 0.0113 AC: 23 AN: 2040

European-Finnish (FIN) AF: 0.000265 AC: 1 AN: 3770

Middle Eastern (MID) AF: 0.0221 AC: 5 AN: 226

European-Non Finnish (NFE) AF: 0.00580 AC: 197 AN: 33980

Other (OTH) AF: 0.00806 AC: 7 AN: 868

Alfa AF: 0.00879 Hom.: 6

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.9
DANN	Benign	0.90
PhyloP100		-6.5
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11755562; hg19: chr6-32009880; COSMIC: COSV64480218; COSMIC: COSV64480218;