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 14 ACMG points: 14P and 0B. 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 (★★).

• 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, 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: Pathogenic. The variant received 14 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AR	NM_000044.6	c.2450-6C>G		splice_region_variant, intron_variant	Intron 6 of 7	ENST00000374690.9	NP_000035.2
AR	NM_001011645.3	c.854-6C>G		splice_region_variant, intron_variant	Intron 7 of 8		NP_001011645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AR	ENST00000374690.9	c.2450-6C>G		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_000044.6	ENSP00000363822.3
AR	ENST00000396044.8	c.2174-865C>G		intron_variant	Intron 4 of 4	1		ENSP00000379359.3
AR	ENST00000396043.4	n.*798-6C>G		splice_region_variant, intron_variant	Intron 7 of 8	1		ENSP00000379358.4
AR	ENST00000612452.5	n.2450-6C>G		splice_region_variant, intron_variant	Intron 6 of 8	5		ENSP00000484033.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Aug 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 28857053). ClinVar contains an entry for this variant (Variation ID: 548144). This variant has been observed in individual(s) with complete androgen insensitivity syndrome (PMID: 28857053). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 6 of the AR gene. It does not directly change the encoded amino acid sequence of the AR protein. -

Androgen resistance syndrome Pathogenic:1

Feb 01, 2018

Institute of Reproductive and Stem Cell Engineering, Central South University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sequence analysis of the AR gene in a AIS patient’s genomic DNA revealed a novel polypyrimidine tract mutation: cytosine to guanine, at position c.2450‑6 (c.2450‑6C>G) in intron 6. The patient’s mother and sister were heterozygous for this mutation, but the mutation was not present in her father or brother, or 100 unrelated normal controls. 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) -

Computational scores

Source: dbNSFP v4.3

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;