chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGC-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000044.6(AR):c.1394_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCG(p.Gly465_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 0.00241 in 559,145 control chromosomes in the GnomAD database, including 141 homozygotes. There are 483 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. G465G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., 68 hem., cov: 0)

Exomes 𝑓: 0.0022 ( 140 hom. 415 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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, 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

AR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant X-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGC-T is Benign according to our data. Variant chrX-67546514-TGGCGGCGGCGGCGGCGGCGGCGGCGGC-T is described in ClinVar as [Benign]. Clinvar id is 1600106.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00343 (285/83055) while in subpopulation AFR AF = 0.0114 (247/21648). AF 95% confidence interval is 0.0102. There are 1 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 68 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.1394_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly465_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9 link	c.1394_1420delGCGGCGGCGGCGGCGGCGGCGGCGGCG	p.Gly465_Gly473del	disruptive_inframe_deletion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

285

AN:

83051

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00154

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000388

Gnomad SAS

AF:

0.0111

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000943

GnomAD4 exome

AF:

0.00223

AC:

1062

AN:

476090

Hom.:

140

AF XY:

0.00351

AC XY:

415

AN XY:

118166

show subpopulations

African (AFR)

AF:

0.0196

AC:

259

AN:

13214

American (AMR)

AF:

0.00291

AC:

AN:

8578

Ashkenazi Jewish (ASJ)

AF:

0.000105

AC:

AN:

9548

East Asian (EAS)

AF:

0.00107

AC:

AN:

14083

South Asian (SAS)

AF:

0.0345

AC:

507

AN:

14712

European-Finnish (FIN)

AF:

0.000183

AC:

AN:

21847

Middle Eastern (MID)

AF:

0.00307

AC:

AN:

1304

European-Non Finnish (NFE)

AF:

0.000519

AC:

193

AN:

372207

Other (OTH)

AF:

0.00262

AC:

AN:

20597

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.688

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

100

<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:

0.00343

AC:

285

AN:

83055

Hom.:

Cov.:

AF XY:

0.00409

AC XY:

AN XY:

16625

show subpopulations

African (AFR)

AF:

0.0114

AC:

247

AN:

21648

American (AMR)

AF:

0.00154

AC:

AN:

7817

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2222

East Asian (EAS)

AF:

0.000390

AC:

AN:

2564

South Asian (SAS)

AF:

0.0112

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:

0.000162

AC:

AN:

43137

Other (OTH)

AF:

0.000929

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.569

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:

0.00

Hom.:

327

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease

Benign:1

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=195/5

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over