chrX-67546514-T-TGGC

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000044.6(AR):c.1418_1420dupGCG(p.Gly473dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 541,667 control chromosomes in the GnomAD database, including 8,015 homozygotes. There are 15,605 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E474E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 2881 hom., 2877 hem., cov: 0)

Exomes 𝑓: 0.18 ( 5134 hom. 12728 hem. )

Consequence

AR
NM_000044.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

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 -16 ACMG points.

BP6

Variant X-67546514-T-TGGC is Benign according to our data. Variant chrX-67546514-T-TGGC is described in ClinVar as [Benign]. Clinvar id is 464786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6 link	c.1418_1420dupGCG	p.Gly473dup	disruptive_inframe_insertion	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.1418_1420dupGCG	p.Gly473dup	disruptive_inframe_insertion	Exon 1 of 8	1	NM_000044.6	ENSP00000363822.3		P10275-1

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

21722

AN:

82953

Hom.:

2882

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.363

Gnomad AMR

AF:

0.239

Gnomad ASJ

AF:

0.326

Gnomad EAS

AF:

0.0676

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.0996

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.299

Gnomad OTH

AF:

0.262

GnomAD4 exome

AF:

0.178

AC:

81685

AN:

458710

Hom.:

5134

Cov.:

AF XY:

0.119

AC XY:

12728

AN XY:

106688

show subpopulations

African (AFR)

AF:

0.109

AC:

1418

AN:

12965

American (AMR)

AF:

0.0136

AC:

116

AN:

8520

Ashkenazi Jewish (ASJ)

AF:

0.0620

AC:

585

AN:

9430

East Asian (EAS)

AF:

0.00888

AC:

125

AN:

14072

South Asian (SAS)

AF:

0.0721

AC:

1044

AN:

14471

European-Finnish (FIN)

AF:

0.0160

AC:

345

AN:

21534

Middle Eastern (MID)

AF:

0.0924

AC:

117

AN:

1266

European-Non Finnish (NFE)

AF:

0.211

AC:

75360

AN:

356376

Other (OTH)

AF:

0.128

AC:

2575

AN:

20076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

2221

4441

6662

8882

11103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.262

AC:

21718

AN:

82957

Hom.:

2881

Cov.:

AF XY:

0.173

AC XY:

2877

AN XY:

16613

show subpopulations

African (AFR)

AF:

0.237

AC:

5119

AN:

21615

American (AMR)

AF:

0.239

AC:

1866

AN:

7797

Ashkenazi Jewish (ASJ)

AF:

0.326

AC:

725

AN:

2222

East Asian (EAS)

AF:

0.0679

AC:

174

AN:

2563

South Asian (SAS)

AF:

0.129

AC:

197

AN:

1522

European-Finnish (FIN)

AF:

0.0996

AC:

236

AN:

2370

Middle Eastern (MID)

AF:

0.247

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.299

AC:

12889

AN:

43105

Other (OTH)

AF:

0.263

AC:

283

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

605

1209

1814

2418

3023

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0613

Hom.:

327

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Partial androgen insensitivity syndrome

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

African/African American population allele frequency is 24.38% (rs760580125, 767/2,962 alleles, 117 homozygotes, 127 hemizygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.2, this variant is classified as BENIGN. Following criteria are met: BA1 -

Androgen resistance syndrome;C1839259:Kennedy disease

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 13, 2019

GeneDx

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

=78/22

polymorphism (auto)

(source)

Splicing

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

Publications

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chrX-67546514-T-TGGC

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