Genetic Variant AR:p.Gly466_Gly473del (chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3BP6_ModerateBS1BS2

The NM_000044.6(AR):c.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG(p.Gly466_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 0.00268 in 559,009 control chromosomes in the GnomAD database, including 125 homozygotes. There are 397 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 (★). Synonymous variant affecting the same amino acid position (i.e. G466G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 2 hom., 44 hem., cov: 0)

Exomes 𝑓: 0.0026 ( 123 hom. 353 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.29

Publications

6 publications found

Variant links:

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

AR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_000044.6

BP6

Variant X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGC-T is described in ClinVar as Benign. ClinVar VariationId is 1167648.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00293 (243/83056) while in subpopulation AFR AF = 0.00697 (151/21650). AF 95% confidence interval is 0.00607. There are 2 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AR	NM_000044.6	MANE Select	c.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly466_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	NP_000035.2
AR	NM_001348063.1		c.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly466_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334992.1	Q9NUA2
AR	NM_001348061.1		c.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly466_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334990.1	Q9NUA2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AR	ENST00000374690.9	TSL:1 MANE Select	c.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly466_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000363822.3	P10275-1
AR	ENST00000396044.8	TSL:1	c.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly466_Gly473del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
AR	ENST00000504326.5	TSL:1	c.1397_1420delGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly466_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

243

AN:

83052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00693

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00243

Gnomad ASJ

AF:

0.00495

Gnomad EAS

AF:

0.000777

Gnomad SAS

AF:

0.00131

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00513

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.00377

GnomAD2 exomes

AF:

0.00532

AC:

200

AN:

37570

AF XY:

0.00339

show subpopulations

Gnomad AFR exome

AF:

0.0871

Gnomad AMR exome

AF:

0.00935

Gnomad ASJ exome

AF:

0.00606

Gnomad EAS exome

AF:

0.0341

Gnomad FIN exome

AF:

0.000132

Gnomad NFE exome

AF:

0.00386

Gnomad OTH exome

AF:

0.00304

GnomAD4 exome

AF:

0.00263

AC:

1253

AN:

475953

Hom.:

123

AF XY:

0.00299

AC XY:

353

AN XY:

118113

show subpopulations

African (AFR)

AF:

0.0111

AC:

146

AN:

13209

American (AMR)

AF:

0.00502

AC:

AN:

8567

Ashkenazi Jewish (ASJ)

AF:

0.00649

AC:

AN:

9547

East Asian (EAS)

AF:

0.00298

AC:

AN:

14094

South Asian (SAS)

AF:

0.00320

AC:

AN:

14709

European-Finnish (FIN)

AF:

0.000137

AC:

AN:

21855

Middle Eastern (MID)

AF:

0.00460

AC:

AN:

1305

European-Non Finnish (NFE)

AF:

0.00227

AC:

845

AN:

372079

Other (OTH)

AF:

0.00287

AC:

AN:

20588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.654

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00293

AC:

243

AN:

83056

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

AN XY:

16626

show subpopulations

African (AFR)

AF:

0.00697

AC:

151

AN:

21650

American (AMR)

AF:

0.00243

AC:

AN:

7817

Ashkenazi Jewish (ASJ)

AF:

0.00495

AC:

AN:

2222

East Asian (EAS)

AF:

0.000780

AC:

AN:

2564

South Asian (SAS)

AF:

0.00131

AC:

AN:

1522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.00125

AC:

AN:

43136

Other (OTH)

AF:

0.00372

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.545

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00162

Hom.:

327

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Androgen resistance syndrome;C1839259:Kennedy disease (1)

AR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=199/1

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over