NM_000044.6:c.1379_1380insGCG

Variant names:

• chrX-67546524-G-GGGC
• rs1555969966
• NM_000044.6:c.1379_1380insGCG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP3 BP6_Moderate

The NM_000044.6(AR):​c.1379_1380insGCG​(p.Gly460_Gly461insArg) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. G460G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 19)
• Consequence: AR NM_000044.6 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.406
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_000044.6
• BP6: Variant X-67546524-G-GGGC is Benign according to our data. Variant chrX-67546524-G-GGGC is described in ClinVar as Benign. ClinVar VariationId is 434261.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.1379_1380insGCG	p.Gly460_Gly461insArg	disruptive_inframe_insertion	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.1379_1380insGCG	p.Gly460_Gly461insArg	disruptive_inframe_insertion	Exon 1 of 4	NP_001334992.1
	AR	NM_001348061.1		c.1379_1380insGCG	p.Gly460_Gly461insArg	disruptive_inframe_insertion	Exon 1 of 4	NP_001334990.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.1379_1380insGCG	p.Gly460_Gly461insArg	disruptive_inframe_insertion	Exon 1 of 8	ENSP00000363822.3
	AR	ENST00000396044.8	TSL:1	c.1379_1380insGCG	p.Gly460_Gly461insArg	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000379359.3
	AR	ENST00000504326.5	TSL:1	c.1379_1380insGCG	p.Gly460_Gly461insArg	disruptive_inframe_insertion	Exon 1 of 4	ENSP00000421155.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 19

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 20, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41
Mutation Taster		=86/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1555969966; hg19: chrX-66766366;