X-67643375-G-C

Variant names:

• chrX-67643375-G-C
• rs1555982879
• NM_000044.6:c.1736G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000044.6(AR):​c.1736G>C​(p.Ser579Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S579R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: AR NM_000044.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.77
• 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000044.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-67643376-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1713192.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 147 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 1.2272 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to androgen insensitivity syndrome, Kennedy disease, complete androgen insensitivity syndrome, partial androgen insensitivity syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant X-67643375-G-C is Pathogenic according to our data. Variant chrX-67643375-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 464791.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.1736G>C	p.Ser579Thr	missense	Exon 2 of 8	NP_000035.2
	AR	NM_001348063.1		c.1736G>C	p.Ser579Thr	missense	Exon 2 of 4	NP_001334992.1
	AR	NM_001348061.1		c.1736G>C	p.Ser579Thr	missense	Exon 2 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.1736G>C	p.Ser579Thr	missense	Exon 2 of 8	ENSP00000363822.3
	AR	ENST00000396044.8	TSL:1	c.1736G>C	p.Ser579Thr	missense	Exon 2 of 5	ENSP00000379359.3
	AR	ENST00000504326.5	TSL:1	c.1736G>C	p.Ser579Thr	missense	Exon 2 of 4	ENSP00000421155.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Androgen resistance syndrome;C1839259:Kennedy disease Pathogenic:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 579 of the AR protein (p.Ser579Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with partial androgen insensitivity syndrome (PMID: 10971094). This variant is also known as S578T. ClinVar contains an entry for this variant (Variation ID: 464791). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AR protein function. Experimental studies have shown that this missense change affects AR function (PMID: 10971094). This variant disrupts the p.Ser579 amino acid residue in AR. Other variant(s) that disrupt this residue have been observed in individuals with AR-related conditions (PMID: 10971094, 20819612, 25613104; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		9.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.96
MVP		1.0
MPC		1.2
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.97
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555982879; hg19: chrX-66863217;