7-75972549-G-A

Variant names:

• chr7-75972549-G-A
• rs17148944
• NM_001395413.1:c.228+88G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001395413.1(POR):​c.228+88G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0924 in 1,270,272 control chromosomes in the GnomAD database, including 6,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (572 hom., cov: 32)
  • Exomes 𝑓: 0.095 (5627 hom.)
• Consequence: POR NM_001395413.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0350
• Publications: 21 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-75972549-G-A is Benign according to our data. Variant chr7-75972549-G-A is described in ClinVar as Benign. ClinVar VariationId is 1264470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395413.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	NM_001395413.1	MANE Select	c.228+88G>A		intron	N/A	NP_001382342.1
	POR	NM_001382655.3		c.282+88G>A		intron	N/A	NP_001369584.2
	POR	NM_001367562.3		c.228+88G>A		intron	N/A	NP_001354491.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POR	ENST00000461988.6	TSL:1 MANE Select	c.228+88G>A		intron	N/A	ENSP00000419970.2
	POR	ENST00000448410.5	TSL:3	n.*19G>A		non_coding_transcript_exon	Exon 3 of 5	ENSP00000399409.2
	POR	ENST00000448410.5	TSL:3	n.*19G>A		3_prime_UTR	Exon 3 of 5	ENSP00000399409.2

Frequencies

GnomAD3 genomes AF: 0.0759 AC: 11556 AN: 152198 Hom.: 571 Cov.: 32

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.0627

Gnomad ASJ AF: 0.0937

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0989

Gnomad OTH AF: 0.0894

GnomAD2 exomes AF: 0.0849 AC: 13324 AN: 156952 AF XY: 0.0918

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.0484

Gnomad ASJ exome AF: 0.0947

Gnomad EAS exome AF: 0.00318

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0925

GnomAD4 exome AF: 0.0946 AC: 105789 AN: 1117956 Hom.: 5627 Cov.: 15 AF XY: 0.0975 AC XY: 54986 AN XY: 563828

African (AFR) AF: 0.0421 AC: 1093 AN: 25968

American (AMR) AF: 0.0520 AC: 1840 AN: 35374

Ashkenazi Jewish (ASJ) AF: 0.0966 AC: 2266 AN: 23450

East Asian (EAS) AF: 0.00159 AC: 55 AN: 34536

South Asian (SAS) AF: 0.153 AC: 11234 AN: 73444

European-Finnish (FIN) AF: 0.0501 AC: 2410 AN: 48084

Middle Eastern (MID) AF: 0.139 AC: 689 AN: 4970

European-Non Finnish (NFE) AF: 0.0995 AC: 81921 AN: 823144

Other (OTH) AF: 0.0874 AC: 4281 AN: 48986

GnomAD4 genome AF: 0.0759 AC: 11565 AN: 152316 Hom.: 572 Cov.: 32 AF XY: 0.0751 AC XY: 5597 AN XY: 74496

African (AFR) AF: 0.0439 AC: 1825 AN: 41570

American (AMR) AF: 0.0626 AC: 958 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0937 AC: 325 AN: 3470

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5180

South Asian (SAS) AF: 0.151 AC: 730 AN: 4826

European-Finnish (FIN) AF: 0.0439 AC: 466 AN: 10626

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0990 AC: 6731 AN: 68022

Other (OTH) AF: 0.0918 AC: 194 AN: 2114

Alfa AF: 0.0886 Hom.: 1107

Bravo AF: 0.0733

Asia WGS AF: 0.0750 AC: 265 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.73
PhyloP100		-0.035
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17148944; hg19: chr7-75601867; COSMIC: COSV67516496;