chrX-67546514-TGGCGGC-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_000044.6(AR):c.1415_1420delGCGGCG(p.Gly472_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 0.0114 in 557,735 control chromosomes in the GnomAD database, including 418 homozygotes. There are 1,145 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G472G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.036 ( 169 hom., 408 hem., cov: 0)

Exomes 𝑓: 0.0070 ( 249 hom. 737 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP3

Nonframeshift variant in repetitive region in NM_000044.6

BP6

Variant X-67546514-TGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

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.1415_1420delGCGGCG	p.Gly472_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	NP_000035.2
AR	NM_001348063.1		c.1415_1420delGCGGCG	p.Gly472_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	NP_001334992.1	Q9NUA2
AR	NM_001348061.1		c.1415_1420delGCGGCG	p.Gly472_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.1415_1420delGCGGCG	p.Gly472_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000363822.3	P10275-1
AR	ENST00000396044.8	TSL:1	c.1415_1420delGCGGCG	p.Gly472_Gly473del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000379359.3	F5GZG9
AR	ENST00000504326.5	TSL:1	c.1415_1420delGCGGCG	p.Gly472_Gly473del	disruptive_inframe_deletion	Exon 1 of 4	ENSP00000421155.1	P10275-3

Frequencies

GnomAD3 genomes

AF:

0.0363

AC:

3014

AN:

83027

Hom.:

169

Cov.:

show subpopulations

Gnomad AFR

AF:

0.127

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.000450

Gnomad EAS

AF:

0.00505

Gnomad SAS

AF:

0.00720

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00513

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.0255

GnomAD4 exome

AF:

0.00700

AC:

3325

AN:

474704

Hom.:

249

AF XY:

0.00628

AC XY:

737

AN XY:

117274

show subpopulations

African (AFR)

AF:

0.122

AC:

1572

AN:

12914

American (AMR)

AF:

0.00596

AC:

AN:

8560

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

9542

East Asian (EAS)

AF:

0.00695

AC:

AN:

13950

South Asian (SAS)

AF:

0.00743

AC:

109

AN:

14679

European-Finnish (FIN)

AF:

0.00212

AC:

AN:

21679

Middle Eastern (MID)

AF:

0.0177

AC:

AN:

1299

European-Non Finnish (NFE)

AF:

0.00298

AC:

1106

AN:

371590

Other (OTH)

AF:

0.0151

AC:

310

AN:

20491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.0364

AC:

3019

AN:

83031

Hom.:

169

Cov.:

AF XY:

0.0245

AC XY:

408

AN XY:

16621

show subpopulations

African (AFR)

AF:

0.127

AC:

2748

AN:

21625

American (AMR)

AF:

0.0139

AC:

109

AN:

7817

Ashkenazi Jewish (ASJ)

AF:

0.000450

AC:

AN:

2222

East Asian (EAS)

AF:

0.00507

AC:

AN:

2564

South Asian (SAS)

AF:

0.00723

AC:

AN:

1522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2382

Middle Eastern (MID)

AF:

0.00575

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.00253

AC:

109

AN:

43136

Other (OTH)

AF:

0.0251

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

188

283

377

471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00

Hom.:

327

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Androgen resistance syndrome;C1839259:Kennedy disease (1)

AR-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=197/3

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