NM_000044.6:c.1403_1420delGCGGCGGCGGCGGCGGCG

Variant names:

• chrX-67546514-TGGCGGCGGCGGCGGCGGC-T
• rs746853821
• NM_000044.6:c.1403_1420delGCGGCGGCGGCGGCGGCG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_000044.6(AR):​c.1403_1420delGCGGCGGCGGCGGCGGCG​(p.Gly468_Gly473del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 558,345 control chromosomes in the GnomAD database, including 1,198 homozygotes. There are 3,999 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (7 hom., 172 hem., cov: 0)
  • Exomes 𝑓: 0.028 (1191 hom. 3827 hem.)
• Consequence: AR NM_000044.6 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29
• Publications: 6 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, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
• Kennedy disease

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

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000044.6
• BP6: Variant X-67546514-TGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGC-T is described in ClinVar as Benign. ClinVar VariationId is 1168910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.011 (912/83045) while in subpopulation NFE AF = 0.0142 (612/43129). AF 95% confidence interval is 0.0133. There are 7 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.1403_1420delGCGGCGGCGGCGGCGGCG	p.Gly468_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.1403_1420delGCGGCGGCGGCGGCGGCG	p.Gly468_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.1403_1420delGCGGCGGCGGCGGCGGCG	p.Gly468_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334990.1	Q9NUA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.1403_1420delGCGGCGGCGGCGGCGGCG	p.Gly468_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.1403_1420delGCGGCGGCGGCGGCGGCG	p.Gly468_Gly473del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.1403_1420delGCGGCGGCGGCGGCGGCG	p.Gly468_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 912 AN: 83041 Hom.: 7 Cov.: 0

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.00666

Gnomad ASJ AF: 0.00945

Gnomad EAS AF: 0.00272

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.00672

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.00660

GnomAD2 exomes AF: 0.0287 AC: 1079 AN: 37570 AF XY: 0.0225

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.0447

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.0256

Gnomad FIN exome AF: 0.00673

Gnomad NFE exome AF: 0.0376

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0276 AC: 13127 AN: 475300 Hom.: 1191 AF XY: 0.0325 AC XY: 3827 AN XY: 117708

African (AFR) AF: 0.00793 AC: 104 AN: 13120

American (AMR) AF: 0.0270 AC: 231 AN: 8557

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 227 AN: 9527

East Asian (EAS) AF: 0.00633 AC: 88 AN: 13901

South Asian (SAS) AF: 0.0455 AC: 667 AN: 14650

European-Finnish (FIN) AF: 0.0121 AC: 265 AN: 21836

Middle Eastern (MID) AF: 0.00613 AC: 8 AN: 1304

European-Non Finnish (NFE) AF: 0.0297 AC: 11061 AN: 371841

Other (OTH) AF: 0.0231 AC: 476 AN: 20564

GnomAD4 genome AF: 0.0110 AC: 912 AN: 83045 Hom.: 7 Cov.: 0 AF XY: 0.0104 AC XY: 172 AN XY: 16615

African (AFR) AF: 0.00499 AC: 108 AN: 21653

American (AMR) AF: 0.00665 AC: 52 AN: 7815

Ashkenazi Jewish (ASJ) AF: 0.00945 AC: 21 AN: 2222

East Asian (EAS) AF: 0.00273 AC: 7 AN: 2563

South Asian (SAS) AF: 0.0131 AC: 20 AN: 1522

European-Finnish (FIN) AF: 0.00672 AC: 16 AN: 2382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.0142 AC: 612 AN: 43129

Other (OTH) AF: 0.00651 AC: 7 AN: 1076

Alfa AF: 0.0131 Hom.: 327

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Androgen resistance syndrome;C1839259:Kennedy disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=199/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs746853821; hg19: chrX-66766356; COSMIC: COSV101019850;