NM_000044.6:c.-547C>T

Variant names:

• chrX-67544600-C-T
• NM_000044.6:c.-547C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The NM_000044.6(AR):​c.-547C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). ClinVar reports functional evidence for this variant: "SCV005356132: In vitro models demonstrate that this variant reduces transcription (Hornig et al 2016. PubMed ID: 27110943).".

• Frequency: Genomes: not found (cov: 20)
• Consequence: AR NM_000044.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.259
• Publications: 3 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, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005356132: In vitro models demonstrate that this variant reduces transcription (Hornig et al 2016. PubMed ID: 27110943).
• PP5: Variant X-67544600-C-T is Pathogenic according to our data. Variant chrX-67544600-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3353504.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.-547C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_000035.2
	AR	NM_000044.6	MANE Select	c.-547C>T		5_prime_UTR	Exon 1 of 8	NP_000035.2
	AR	NM_001348063.1		c.-547C>T		upstream_gene	N/A	NP_001334992.1	Q9NUA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.-547C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000374690.9	TSL:1 MANE Select	c.-547C>T		5_prime_UTR	Exon 1 of 8	ENSP00000363822.3	P10275-1
	AR	ENST00000396043.4	TSL:1	n.-547C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000379358.4	A0A7I2PS51

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	AR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.82
PhyloP100		0.26
PromoterAI		0.15	Neutral

Splicing

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

Other links and lift over

hg19: chrX-66764442;