chr9-124503358-CACAG-ACAGGTCCAGGTC

Position:

• chr9-124503358-CACAG-ACAGGTCCAGGTC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004959.5(NR5A1):​c.34_38delinsGACCTGGACCTGT​(p.Leu12AspfsTer66) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR5A1 NM_004959.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.79

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 142 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-124503358-CACAG-ACAGGTCCAGGTC is Pathogenic according to our data. Variant chr9-124503358-CACAG-ACAGGTCCAGGTC is described in ClinVar as [Pathogenic]. Clinvar id is 436032.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR5A1	NM_004959.5	c.34_38delinsGACCTGGACCTGT	p.Leu12AspfsTer66	frameshift_variant	2/7	ENST00000373588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR5A1	ENST00000373588.9	c.34_38delinsGACCTGGACCTGT	p.Leu12AspfsTer66	frameshift_variant	2/7	1	NM_004959.5	P1
NR5A1	ENST00000455734.1	c.34_38delinsGACCTGGACCTGT	p.Leu12AspfsTer66	frameshift_variant	2/4	3
NR5A1	ENST00000620110.4	c.34_38delinsGACCTGGACCTGT	p.Leu12AspfsTer66	frameshift_variant	2/6	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: criteria provided, single submitter

Submissions by phenotype

46,XY sex reversal 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 10, 2017

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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: rs1554721883; hg19: chr9-127265637;