rs562025438

Variant names:

• chr6-32041310-C-T
• rs562025438
• ENST00000490077.5:n.2601G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The ENST00000490077.5(TNXB):​n.2601G>A variant causes a non coding transcript exon 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 0.018 (2 hom., cov: 23)
  • Exomes 𝑓: 0.024 (23 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB ENST00000490077.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.189
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 6-32041310-C-T is Benign according to our data. Variant chr6-32041310-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 261093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.*39G>A		3_prime_UTR_variant	Exon 44 of 44	ENST00000644971.2	NP_001352205.1
CYP21A2	NM_000500.9	c.*176C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000644719.2	NP_000491.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.*39G>A		3_prime_UTR_variant	Exon 44 of 44		NM_001365276.2	ENSP00000496448.1
CYP21A2	ENST00000644719.2	c.*176C>T		3_prime_UTR_variant	Exon 10 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2626 AN: 147624 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00463

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.00976

Gnomad EAS AF: 0.00362

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0245

GnomAD2 exomes AF: 0.0207 AC: 2995 AN: 144950 AF XY: 0.0222

Gnomad AFR exome AF: 0.00293

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.00846

Gnomad EAS exome AF: 0.00421

Gnomad FIN exome AF: 0.0341

Gnomad NFE exome AF: 0.0251

Gnomad OTH exome AF: 0.0185

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0240 AC: 15183 AN: 633796 Hom.: 23 Cov.: 8 AF XY: 0.0242 AC XY: 8160 AN XY: 336810

African (AFR) AF: 0.00301 AC: 52 AN: 17274

American (AMR) AF: 0.0153 AC: 531 AN: 34736

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 165 AN: 20484

East Asian (EAS) AF: 0.00524 AC: 170 AN: 32460

South Asian (SAS) AF: 0.0252 AC: 1624 AN: 64436

European-Finnish (FIN) AF: 0.0346 AC: 1625 AN: 46980

Middle Eastern (MID) AF: 0.0144 AC: 39 AN: 2714

European-Non Finnish (NFE) AF: 0.0269 AC: 10250 AN: 381644

Other (OTH) AF: 0.0220 AC: 727 AN: 33068

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0178 AC: 2625 AN: 147742 Hom.: 2 Cov.: 23 AF XY: 0.0179 AC XY: 1287 AN XY: 71956

African (AFR) AF: 0.00351 AC: 141 AN: 40170

American (AMR) AF: 0.0211 AC: 316 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.00976 AC: 33 AN: 3382

East Asian (EAS) AF: 0.00363 AC: 18 AN: 4962

South Asian (SAS) AF: 0.0201 AC: 89 AN: 4422

European-Finnish (FIN) AF: 0.0322 AC: 329 AN: 10228

Middle Eastern (MID) AF: 0.0138 AC: 4 AN: 290

European-Non Finnish (NFE) AF: 0.0247 AC: 1642 AN: 66462

Other (OTH) AF: 0.0243 AC: 49 AN: 2018

Alfa AF: 0.0187 Hom.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.36
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

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: rs562025438; hg19: chr6-32009087;