rs11423899

Variant names:

• chr6-32042415-C-CT
• rs11423899
• NM_001365276.2:c.12210+39dupA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001365276.2(TNXB):​c.12210+39dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0015 (976 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.69
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 6-32042415-C-CT is Benign according to our data. Variant chr6-32042415-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 261121.Status of the report is criteria_provided_single_submitter, 1 stars.

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.12210+39dupA		intron	N/A	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.12951+39dupA		intron	N/A	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.12204+39dupA		intron	N/A	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.12210+39_12210+40insA		intron	N/A	ENSP00000496448.1	P22105-3
	TNXB	ENST00000451343.4	TSL:1	c.1497+39_1497+40insA		intron	N/A	ENSP00000407685.1	P22105-2
	TNXB	ENST00000490077.5	TSL:1	n.2037+39_2037+40insA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 191 AN: 135452 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00313

Gnomad AMI AF: 0.00246

Gnomad AMR AF: 0.00161

Gnomad ASJ AF: 0.000620

Gnomad EAS AF: 0.000625

Gnomad SAS AF: 0.00197

Gnomad FIN AF: 0.0000990

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000716

Gnomad OTH AF: 0.00161

GnomAD2 exomes AF: 0.0000731 AC: 18 AN: 246348 AF XY: 0.000120

Gnomad AFR exome AF: 0.000264

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.000331

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00147 AC: 2070 AN: 1405160 Hom.: 976 Cov.: 32 AF XY: 0.00184 AC XY: 1286 AN XY: 699232

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00613 AC: 182 AN: 29702

American (AMR) AF: 0.00175 AC: 77 AN: 44102

Ashkenazi Jewish (ASJ) AF: 0.00229 AC: 58 AN: 25354

East Asian (EAS) AF: 0.000773 AC: 30 AN: 38792

South Asian (SAS) AF: 0.0113 AC: 898 AN: 79764

European-Finnish (FIN) AF: 0.000438 AC: 23 AN: 52502

Middle Eastern (MID) AF: 0.00143 AC: 8 AN: 5592

European-Non Finnish (NFE) AF: 0.000672 AC: 720 AN: 1071368

Other (OTH) AF: 0.00128 AC: 74 AN: 57984

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000826006), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00141 AC: 191 AN: 135568 Hom.: 0 Cov.: 20 AF XY: 0.00151 AC XY: 100 AN XY: 66076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00312 AC: 104 AN: 33304

American (AMR) AF: 0.00161 AC: 23 AN: 14274

Ashkenazi Jewish (ASJ) AF: 0.000620 AC: 2 AN: 3228

East Asian (EAS) AF: 0.000627 AC: 3 AN: 4788

South Asian (SAS) AF: 0.00197 AC: 8 AN: 4068

European-Finnish (FIN) AF: 0.0000990 AC: 1 AN: 10100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.000716 AC: 45 AN: 62850

Other (OTH) AF: 0.00160 AC: 3 AN: 1878

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000325 Hom.: 4

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
PhyloP100		-3.7
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11423899; hg19: chr6-32010192;