X-67545316-T-TGCTGCA

Variant names:

• chrX-67545316-T-TGCTGCA
• rs1206863775
• NM_000044.6:c.172_173insTGCAGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BS2_Supporting

The NM_000044.6(AR):​c.172_173insTGCAGC​(p.Leu57_Gln58insLeuGln) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,003,926 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., 0 hem., cov: 0)
  • Exomes 𝑓: 0.000032 (0 hom. 3 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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 -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000044.6
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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_173insTGCAGC	p.Leu57_Gln58insLeuGln	disruptive_inframe_insertion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.172_173insTGCAGC	p.Leu57_Gln58insLeuGln	disruptive_inframe_insertion	Exon 1 of 4	NP_001334992.1
	AR	NM_001348061.1		c.172_173insTGCAGC	p.Leu57_Gln58insLeuGln	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_173insTGCAGC	p.Leu57_Gln58insLeuGln	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000363822.3
	AR	ENST00000396044.8	TSL:1	c.172_173insTGCAGC	p.Leu57_Gln58insLeuGln	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000379359.3
	AR	ENST00000504326.5	TSL:1	c.172_173insTGCAGC	p.Leu57_Gln58insLeuGln	disruptive_inframe_insertion	Exon 1 of 4	ENSP00000421155.1

Frequencies

GnomAD3 genomes AF: 0.0000900 AC: 6 AN: 66636 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000160

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: 0.0000864

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000320 AC: 30 AN: 937303 Hom.: 0 Cov.: 40 AF XY: 0.0000102 AC XY: 3 AN XY: 295395

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

African (AFR) AF: 0.0000421 AC: 1 AN: 23762

American (AMR) AF: 0.0000773 AC: 2 AN: 25861

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16268

East Asian (EAS) AF: 0.000211 AC: 6 AN: 28383

South Asian (SAS) AF: 0.0000442 AC: 2 AN: 45244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36188

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

European-Non Finnish (NFE) AF: 0.0000250 AC: 18 AN: 719100

Other (OTH) AF: 0.0000251 AC: 1 AN: 39901

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000278999), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000901 AC: 6 AN: 66623 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8259

African (AFR) AF: 0.000160 AC: 3 AN: 18799

American (AMR) AF: 0.00 AC: 0 AN: 5236

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1843

South Asian (SAS) AF: 0.00 AC: 0 AN: 901

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 133

European-Non Finnish (NFE) AF: 0.0000864 AC: 3 AN: 34713

Other (OTH) AF: 0.00 AC: 0 AN: 812

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

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;