rs1204038

Variant names:

• chrX-67568383-G-A
• rs1204038
• NM_000044.6:c.1616+21621G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000044.6(AR):​c.1616+21621G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 110,698 control chromosomes in the GnomAD database, including 8,949 homozygotes. There are 10,288 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.34 (8949 hom., 10288 hem., cov: 22)
• Consequence: AR NM_000044.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.533
• Publications: 22 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, 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-67568383-G-A is Benign according to our data. Variant chrX-67568383-G-A is described in ClinVar as Benign. ClinVar VariationId is 1645141.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.852 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.1616+21621G>A		intron_variant	Intron 1 of 7	ENST00000374690.9	NP_000035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.1616+21621G>A		intron_variant	Intron 1 of 7	1	NM_000044.6	ENSP00000363822.3

Frequencies

GnomAD3 genomes AF: 0.341 AC: 37770 AN: 110644 Hom.: 8940 Cov.: 22

Gnomad AFR AF: 0.860

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.00171

Gnomad SAS AF: 0.0780

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.294

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.342 AC: 37832 AN: 110698 Hom.: 8949 Cov.: 22 AF XY: 0.312 AC XY: 10288 AN XY: 32998

African (AFR) AF: 0.860 AC: 25961 AN: 30173

American (AMR) AF: 0.165 AC: 1722 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 305 AN: 2639

East Asian (EAS) AF: 0.00171 AC: 6 AN: 3502

South Asian (SAS) AF: 0.0774 AC: 206 AN: 2661

European-Finnish (FIN) AF: 0.114 AC: 682 AN: 5969

Middle Eastern (MID) AF: 0.213 AC: 46 AN: 216

European-Non Finnish (NFE) AF: 0.159 AC: 8389 AN: 52882

Other (OTH) AF: 0.291 AC: 438 AN: 1507

Alfa AF: 0.240 Hom.: 7449

Bravo AF: 0.366

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.40
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1204038; hg19: chrX-66788225;