9-124500591-CC-AG

Variant names:

• chr9-124500591-CC-AG
• NM_004959.5:c.368_369delGGinsCT
• NR5A1 p.Gly123Ala

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_004959.5(NR5A1):​c.368_369delGGinsCT​(p.Gly123Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G123W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR5A1 NM_004959.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07
• Publications: 0 publications found

Genes affected

NR5A1 (HGNC:7983): (nuclear receptor subfamily 5 group A member 1) The protein encoded by this gene is a transcriptional activator involved in sex determination. The encoded protein binds DNA as a monomer. Defects in this gene are a cause of XY sex reversal with or without adrenal failure as well as adrenocortical insufficiency without ovarian defect. [provided by RefSeq, Jul 2008]

NR5A1 Gene-Disease associations (from GenCC):

• 46,XX sex reversal 4

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46,XY sex reversal 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• premature ovarian failure 7

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XX ovotesticular disorder of sex development

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XX sex reversal 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 46 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.3359 (below the threshold of 3.09). Trascript score misZ: 2.4094 (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XY sex reversal 3, 46,XY complete gonadal dysgenesis, 46,XX ovotesticular disorder of sex development, premature ovarian failure 7, 46,XX sex reversal 4, spermatogenic failure 8, 46 XX gonadal dysgenesis, 46,XX sex reversal 1, male infertility with azoospermia or oligozoospermia due to single gene mutation, 46,XY partial gonadal dysgenesis.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004959.5. 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
	NR5A1	NM_004959.5	MANE Select	c.368_369delGGinsCT	p.Gly123Ala	missense	N/A	NP_004950.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR5A1	ENST00000373588.9	TSL:1 MANE Select	c.368_369delGGinsCT	p.Gly123Ala	missense	N/A	ENSP00000362690.4	Q13285
	NR5A1	ENST00000950385.1		c.368_369delGGinsCT	p.Gly123Ala	missense	N/A	ENSP00000620444.1
	NR5A1	ENST00000911688.1		c.368_369delGGinsCT	p.Gly123Ala	missense	N/A	ENSP00000581746.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-127262870;