NM_000044.6:c.1412_1420dupGCGGCGGCG

Variant names:

• chrX-67546514-T-TGGCGGCGGC
• rs746853821
• NM_000044.6:c.1412_1420dupGCGGCGGCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_000044.6(AR):​c.1412_1420dupGCGGCGGCG​(p.Gly471_Gly473dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E474E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0094 (12 hom., 94 hem., cov: 0)
  • Exomes 𝑓: 0.0055 (22 hom. 583 hem.)
  • Failed GnomAD Quality Control
• Consequence: AR NM_000044.6 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_000044.6
• BP6: Variant X-67546514-T-TGGCGGCGGC is Benign according to our data. Variant chrX-67546514-T-TGGCGGCGGC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 638387.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00937 (778/83055) while in subpopulation AFR AF = 0.0171 (370/21649). AF 95% confidence interval is 0.0157. There are 12 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.1412_1420dupGCGGCGGCG	p.Gly471_Gly473dup	disruptive_inframe_insertion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.1412_1420dupGCGGCGGCG	p.Gly471_Gly473dup	disruptive_inframe_insertion	Exon 1 of 4	NP_001334992.1	Q9NUA2
	AR	NM_001348061.1		c.1412_1420dupGCGGCGGCG	p.Gly471_Gly473dup	disruptive_inframe_insertion	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.1412_1420dupGCGGCGGCG	p.Gly471_Gly473dup	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.1412_1420dupGCGGCGGCG	p.Gly471_Gly473dup	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
	AR	ENST00000504326.5	TSL:1	c.1412_1420dupGCGGCGGCG	p.Gly471_Gly473dup	disruptive_inframe_insertion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 778 AN: 83051 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.0409

Gnomad AMR AF: 0.00922

Gnomad ASJ AF: 0.00225

Gnomad EAS AF: 0.00505

Gnomad SAS AF: 0.0144

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.0103

Gnomad NFE AF: 0.00542

Gnomad OTH AF: 0.0104

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00550 AC: 2614 AN: 475547 Hom.: 22 Cov.: 25 AF XY: 0.00495 AC XY: 583 AN XY: 117847

African (AFR) AF: 0.00999 AC: 132 AN: 13211

American (AMR) AF: 0.000233 AC: 2 AN: 8585

Ashkenazi Jewish (ASJ) AF: 0.000838 AC: 8 AN: 9549

East Asian (EAS) AF: 0.000709 AC: 10 AN: 14099

South Asian (SAS) AF: 0.00544 AC: 80 AN: 14709

European-Finnish (FIN) AF: 0.000457 AC: 10 AN: 21872

Middle Eastern (MID) AF: 0.00536 AC: 7 AN: 1306

European-Non Finnish (NFE) AF: 0.00605 AC: 2249 AN: 371630

Other (OTH) AF: 0.00563 AC: 116 AN: 20586

GnomAD4 genome AF: 0.00937 AC: 778 AN: 83055 Hom.: 12 Cov.: 0 AF XY: 0.00565 AC XY: 94 AN XY: 16629

African (AFR) AF: 0.0171 AC: 370 AN: 21649

American (AMR) AF: 0.00921 AC: 72 AN: 7817

Ashkenazi Jewish (ASJ) AF: 0.00225 AC: 5 AN: 2222

East Asian (EAS) AF: 0.00507 AC: 13 AN: 2564

South Asian (SAS) AF: 0.0145 AC: 22 AN: 1522

European-Finnish (FIN) AF: 0.0118 AC: 28 AN: 2381

Middle Eastern (MID) AF: 0.0115 AC: 2 AN: 174

European-Non Finnish (NFE) AF: 0.00542 AC: 234 AN: 43137

Other (OTH) AF: 0.0102 AC: 11 AN: 1076

Alfa AF: 0.00 Hom.: 327

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Androgen resistance syndrome (1)
-	-	1	AR-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=78/22	polymorphism

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;