rs544604053

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-32041892-C-G
• chr6-32041892-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001365276.2(TNXB):​c.12512G>C​(p.Arg4171Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4171H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39348784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.12512G>C	p.Arg4171Pro	missense_variant	Exon 43 of 44	ENST00000644971.2	NP_001352205.1
CYP21A2	NM_000500.9	c.*758C>G		downstream_gene_variant		ENST00000644719.2	NP_000491.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.12512G>C	p.Arg4171Pro	missense_variant	Exon 43 of 44		NM_001365276.2	ENSP00000496448.1
CYP21A2	ENST00000644719.2	c.*758C>G		downstream_gene_variant			NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome AF: 0.00000168 AC: 1 AN: 596980 Hom.: 0 Cov.: 6 AF XY: 0.00000318 AC XY: 1 AN XY: 314622

African (AFR) AF: 0.00 AC: 0 AN: 17332

American (AMR) AF: 0.00 AC: 0 AN: 33174

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 62692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2556

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 360598

Other (OTH) AF: 0.0000315 AC: 1 AN: 31776

GnomAD4 genome Cov.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;T;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	.;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Benign	-0.94	T
PhyloP100		0.23
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.4	.;.;D;D;.
REVEL	Uncertain	0.33
Sift	Benign	0.18	.;.;T;T;.
Sift4G	Uncertain	0.0030	.;.;D;D;D
Vest4		0.40, 0.54
MVP		0.39
MPC		3.7
ClinPred		0.89	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.77
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -19

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

Other links and lift over

dbSNP: rs544604053; hg19: chr6-32009669;