X-67722821-C-G

Variant names:

• chrX-67722821-C-G
• rs754515125
• NM_000044.6:c.2450-6C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000044.6(AR):​c.2450-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000680459: To determine the functional consequences of the mutation, the resulting messenger RNA (mRNA) transcript was analyzed. Subsequent sequence analysis of the RT–PCR (reverse transcription polymerase chain reaction) products demonstrated an insertion of 5 nucleotides in the junction between exons 6 and 7 (c.2449–c.2450insATCAG). The mutation generated a new splice acceptor site upstream of the original site, resulting in incorrect pre–mRNA splicing. The aberrant splicing transcript resulted in the introduction of a premature stop codon, thus producing a truncated protein (823 amino acids, p.Ile817Asnfs*8)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AR NM_000044.6 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.731
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000680459: To determine the functional consequences of the mutation, the resulting messenger RNA (mRNA) transcript was analyzed. Subsequent sequence analysis of the RT–PCR (reverse transcription polymerase chain reaction) products demonstrated an insertion of 5 nucleotides in the junction between exons 6 and 7 (c.2449–c.2450insATCAG). The mutation generated a new splice acceptor site upstream of the original site, resulting in incorrect pre–mRNA splicing. The aberrant splicing transcript resulted in the introduction of a premature stop codon, thus producing a truncated protein (823 amino acids, p.Ile817Asnfs*8); SCV004573378: Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 28857053).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-67722821-C-G is Pathogenic according to our data. Variant chrX-67722821-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 548144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	NM_000044.6	MANE Select	c.2450-6C>G		splice_region intron	N/A	NP_000035.2
	AR	NM_001011645.3		c.854-6C>G		splice_region intron	N/A	NP_001011645.1	Q9NUA2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AR	ENST00000374690.9	TSL:1 MANE Select	c.2450-6C>G		splice_region intron	N/A	ENSP00000363822.3	P10275-1
	AR	ENST00000396044.8	TSL:1	c.2174-865C>G		intron	N/A	ENSP00000379359.3	F5GZG9
	AR	ENST00000396043.4	TSL:1	n.*798-6C>G		splice_region intron	N/A	ENSP00000379358.4	A0A7I2PS51

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Androgen resistance syndrome (1)
1	-	-	Androgen resistance syndrome;C1839259:Kennedy disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.81
PhyloP100		-0.73
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 1
DS_AL_spliceai		0.27		Position offset: 6

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

Other links and lift over

dbSNP: rs754515125; hg19: chrX-66942663;