X-67608543-A-G

Variant names:

• chrX-67608543-A-G
• rs4827545
• NM_000044.6:c.1617-34713A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000044.6(AR):​c.1617-34713A>G variant causes a intron 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.

• Frequency:
  • Genomes: 𝑓 0.73 (22135 hom., 24336 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.316
• Publications: 9 publications found

Genes affected

AR (HGNC:644): (androgen receptor) The androgen receptor gene is more than 90 kb long and codes for a protein that has 3 major functional domains: the N-terminal domain, DNA-binding domain, and androgen-binding domain. The protein functions as a steroid-hormone activated transcription factor. Upon binding the hormone ligand, the receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen responsive genes. This gene contains 2 polymorphic trinucleotide repeat segments that encode polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. Expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy's disease). Mutations in this gene are also associated with complete androgen insensitivity (CAIS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2017]

AR Gene-Disease associations (from GenCC):

• androgen insensitivity syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Kennedy disease

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• partial androgen insensitivity syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• complete androgen insensitivity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000044.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.1617-34713A>G		intron	N/A	NP_000035.2
	AR	NM_001348063.1		c.1617-34713A>G		intron	N/A	NP_001334992.1
	AR	NM_001348061.1		c.1617-34713A>G		intron	N/A	NP_001334990.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.1617-34713A>G		intron	N/A	ENSP00000363822.3
	AR	ENST00000396044.8	TSL:1	c.1617-34713A>G		intron	N/A	ENSP00000379359.3
	AR	ENST00000504326.5	TSL:1	c.1617-34713A>G		intron	N/A	ENSP00000421155.1

Frequencies

GnomAD3 genomes AF: 0.733 AC: 80885 AN: 110376 Hom.: 22145 Cov.: 23

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.861

Gnomad ASJ AF: 0.885

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.917

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.811

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.764

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.733 AC: 80903 AN: 110430 Hom.: 22135 Cov.: 23 AF XY: 0.745 AC XY: 24336 AN XY: 32676

African (AFR) AF: 0.409 AC: 12447 AN: 30433

American (AMR) AF: 0.861 AC: 8882 AN: 10313

Ashkenazi Jewish (ASJ) AF: 0.885 AC: 2334 AN: 2636

East Asian (EAS) AF: 0.999 AC: 3493 AN: 3498

South Asian (SAS) AF: 0.917 AC: 2362 AN: 2576

European-Finnish (FIN) AF: 0.880 AC: 5088 AN: 5782

Middle Eastern (MID) AF: 0.808 AC: 172 AN: 213

European-Non Finnish (NFE) AF: 0.841 AC: 44379 AN: 52799

Other (OTH) AF: 0.767 AC: 1153 AN: 1504

Alfa AF: 0.792 Hom.: 35913

Bravo AF: 0.725

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.49
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism (auto)

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: rs4827545; hg19: chrX-66828385;