rs121918654

chr9-124503218-GC-TT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 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 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004959.5
• 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 ClinVar as [Pathogenic]. Clinvar id is 1202588.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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	UniProt
NR5A1	NM_004959.5	c.104_105delinsAA	p.Gly35Glu	missense_variant, splice_region_variant	3/7	ENST00000373588.9

Ensembl

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

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;