rs751713917

Variant names:

• chr8-64624401-A-G
• rs751713917
• NM_004820.5:c.259+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004820.5(CYP7B1):​c.259+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYP7B1 NM_004820.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.23
• Publications: 3 publications found

Genes affected

CYP7B1 (HGNC:2652): (cytochrome P450 family 7 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway of extrahepatic tissues, which converts cholesterol to bile acids. This enzyme likely plays a minor role in total bile acid synthesis, but may also be involved in the development of atherosclerosis, neurosteroid metabolism and sex hormone synthesis. Mutations in this gene have been associated with hereditary spastic paraplegia (SPG5 or HSP), an autosomal recessive disorder. [provided by RefSeq, Apr 2016]

CYP7B1 Gene-Disease associations (from GenCC):

• CYP7B1-related disorder of oxysterol accumulation

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital bile acid synthesis defect 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 5A

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-64624401-A-G is Pathogenic according to our data. Variant chr8-64624401-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004820.5. 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
	CYP7B1	NM_004820.5	MANE Select	c.259+2T>C		splice_donor intron	N/A	NP_004811.1	O75881
	CYP7B1	NM_001324112.2		c.259+2T>C		splice_donor intron	N/A	NP_001311041.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7B1	ENST00000310193.4	TSL:1 MANE Select	c.259+2T>C		splice_donor intron	N/A	ENSP00000310721.3	O75881
	CYP7B1	ENST00000864436.1		c.412+2T>C		splice_donor intron	N/A	ENSP00000534495.1
	CYP7B1	ENST00000864435.1		c.259+2T>C		splice_donor intron	N/A	ENSP00000534494.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251300 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461398 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111666

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000801 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary spastic paraplegia 5A (3)
1	-	-	Hereditary spastic paraplegia 5A;C3151147:Congenital bile acid synthesis defect 3 (1)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
GERP RS		4.5
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 2

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

Other links and lift over

dbSNP: rs751713917; hg19: chr8-65536958;