rs121918654

Positions:

• chr9-124503218-GC-TT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_004959.5(NR5A1):​c.104_105delinsAA​(p.Gly35Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G35D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR5A1 NM_004959.5 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-124503219-C-T is described in Lovd as [Likely_pathogenic].
• PP5: Variant 9-124503218-GC-TT is Pathogenic according to our data. Variant chr9-124503218-GC-TT is described in ClinVar as [Pathogenic]. Clinvar id is 12794.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR5A1	NM_004959.5	c.104_105delinsAA	p.Gly35Glu	missense_variant, splice_region_variant	3/7	ENST00000373588.9	NP_004950.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR5A1	ENST00000373588.9	c.104_105delinsAA	p.Gly35Glu	missense_variant, splice_region_variant	3/7	1	NM_004959.5	ENSP00000362690	P1
NR5A1	ENST00000455734.1	c.104_105delinsAA	p.Gly35Glu	missense_variant, splice_region_variant	3/4	3		ENSP00000393245
NR5A1	ENST00000620110.4	c.104_105delinsAA	p.Gly35Glu	missense_variant, splice_region_variant	3/6	5		ENSP00000483309

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

46,XY sex reversal 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 24, 2003

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918654; hg19: chr9-127265497;