X-67545316-T-TGCTGCAGCAGCAGCA

Variant names:

• chrX-67545316-T-TGCTGCAGCAGCAGCA
• rs1206863775
• NM_000044.6:c.172_173insTGCAGCAGCAGCAGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_000044.6(AR):​c.172_173insTGCAGCAGCAGCAGC​(p.Leu57_Gln58insLeuGlnGlnGlnGln) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., 1 hem., cov: 0)
  • Exomes 𝑓: 0.000011 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.337
• Publications: 2 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 -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000044.6

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.172_173insTGCAGCAGCAGCAGC	p.Leu57_Gln58insLeuGlnGlnGlnGln	disruptive_inframe_insertion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.172_173insTGCAGCAGCAGCAGC	p.Leu57_Gln58insLeuGlnGlnGlnGln	disruptive_inframe_insertion	Exon 1 of 4	NP_001334992.1
	AR	NM_001348061.1		c.172_173insTGCAGCAGCAGCAGC	p.Leu57_Gln58insLeuGlnGlnGlnGln	disruptive_inframe_insertion	Exon 1 of 4	NP_001334990.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.172_173insTGCAGCAGCAGCAGC	p.Leu57_Gln58insLeuGlnGlnGlnGln	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000363822.3
	AR	ENST00000396044.8	TSL:1	c.172_173insTGCAGCAGCAGCAGC	p.Leu57_Gln58insLeuGlnGlnGlnGln	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000379359.3
	AR	ENST00000504326.5	TSL:1	c.172_173insTGCAGCAGCAGCAGC	p.Leu57_Gln58insLeuGlnGlnGlnGln	disruptive_inframe_insertion	Exon 1 of 4	ENSP00000421155.1

Frequencies

GnomAD3 genomes AF: 0.0000150 AC: 1 AN: 66636 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000288

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000107 AC: 10 AN: 937329 Hom.: 0 Cov.: 40 AF XY: 0.00000677 AC XY: 2 AN XY: 295421

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

African (AFR) AF: 0.00 AC: 0 AN: 23760

American (AMR) AF: 0.0000387 AC: 1 AN: 25861

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16269

East Asian (EAS) AF: 0.000211 AC: 6 AN: 28386

South Asian (SAS) AF: 0.00 AC: 0 AN: 45251

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36191

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2596

European-Non Finnish (NFE) AF: 0.00000278 AC: 2 AN: 719113

Other (OTH) AF: 0.0000251 AC: 1 AN: 39902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000490125), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000150 AC: 1 AN: 66636 Hom.: 0 Cov.: 0 AF XY: 0.000121 AC XY: 1 AN XY: 8246

African (AFR) AF: 0.00 AC: 0 AN: 18780

American (AMR) AF: 0.00 AC: 0 AN: 5228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1715

East Asian (EAS) AF: 0.00 AC: 0 AN: 1853

South Asian (SAS) AF: 0.00 AC: 0 AN: 912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2025

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 153

European-Non Finnish (NFE) AF: 0.0000288 AC: 1 AN: 34722

Other (OTH) AF: 0.00 AC: 0 AN: 802

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Androgen resistance syndrome;C1839259:Kennedy disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34

Splicing

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

Other links and lift over

dbSNP: rs1206863775; hg19: chrX-66765158;