chr7-75984963-G-GCCC

Variant names:

• chr7-75984963-G-GCCC
• rs797045899
• NM_001395413.1:c.1239+8_1239+10dupCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000461988.6(POR):​c.1239+5_1239+6insCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,425,456 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: POR ENST00000461988.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 0 publications found

Genes affected

POR (HGNC:9208): (cytochrome p450 oxidoreductase) This gene encodes an endoplasmic reticulum membrane oxidoreductase that is essential for multiple metabolic processes, including reactions catalyzed by cytochrome P450 proteins for metabolism of steroid hormones, drugs and xenobiotics. The encoded protein has a flavin adenine dinucleotide (FAD)-binding domain and a flavodoxin-like domain which bind two cofactors, FAD and FMN, that allow it to donate electrons directly from NADPH to all microsomal P450 enzymes. Mutations in this gene cause a complex set of disorders, including apparent combined P450C17 and P450C21 deficiency, amenorrhea and disordered steroidogenesis, congenital adrenal hyperplasia and Antley-Bixler syndrome, that resemble those caused by defects in steroid metabolizing enzymes such as aromatase, 21-hydroxylase, and 17 alpha-hydroxylase. [provided by RefSeq, Aug 2020]

POR Gene-Disease associations (from GenCC):

• Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics
• congenital adrenal hyperplasia due to cytochrome P450 oxidoreductase deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000461988.6. 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
	POR	NM_001395413.1	MANE Select	c.1239+8_1239+10dupCCC		intron	N/A	NP_001382342.1
	POR	NM_001382655.3		c.1293+8_1293+10dupCCC		intron	N/A	NP_001369584.2
	POR	NM_001367562.3		c.1239+8_1239+10dupCCC		intron	N/A	NP_001354491.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	ENST00000461988.6	TSL:1 MANE Select	c.1239+5_1239+6insCCC		splice_region intron	N/A	ENSP00000419970.2
	POR	ENST00000447222.5	TSL:5	c.1398+5_1398+6insCCC		splice_region intron	N/A	ENSP00000393527.1
	POR	ENST00000910548.1		c.1239+5_1239+6insCCC		splice_region intron	N/A	ENSP00000580607.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425456 Hom.: 0 Cov.: 44 AF XY: 0.00000142 AC XY: 1 AN XY: 704846

African (AFR) AF: 0.0000302 AC: 1 AN: 33100

American (AMR) AF: 0.00 AC: 0 AN: 43432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24128

East Asian (EAS) AF: 0.00 AC: 0 AN: 38708

South Asian (SAS) AF: 0.00 AC: 0 AN: 82414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5548

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092416

Other (OTH) AF: 0.00 AC: 0 AN: 58802

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

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

Other links and lift over

dbSNP: rs797045899; hg19: chr7-75614281;