8-64596305-A-C

Variant names:

• chr8-64596305-A-C
• rs118000312
• NM_004820.5:c.*337T>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004820.5(CYP7B1):​c.*337T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 192,882 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (57 hom., cov: 33)
  • Exomes 𝑓: 0.028 (23 hom.)
• Consequence: CYP7B1 NM_004820.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.23

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 8-64596305-A-C is Benign according to our data. Variant chr8-64596305-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 363576.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0229 (3483/152288) while in subpopulation SAS AF= 0.0465 (224/4814). AF 95% confidence interval is 0.0415. There are 57 homozygotes in gnomad4. There are 1698 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP7B1	NM_004820.5	c.*337T>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000310193.4	NP_004811.1
CYP7B1	XM_017014002.2	c.*337T>G		3_prime_UTR_variant	Exon 7 of 7		XP_016869491.1
CYP7B1	NM_001324112.2	c.1234-6461T>G		intron_variant	Intron 5 of 6		NP_001311041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP7B1	ENST00000310193	c.*337T>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_004820.5	ENSP00000310721.3
CYP7B1	ENST00000523954.1	n.508-6461T>G		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3476 AN: 152168 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00481

Gnomad SAS AF: 0.0467

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0315

Gnomad OTH AF: 0.0267

GnomAD4 exome AF: 0.0278 AC: 1128 AN: 40594 Hom.: 23 Cov.: 0 AF XY: 0.0293 AC XY: 661 AN XY: 22544

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0174

Gnomad4 ASJ exome AF: 0.0541

Gnomad4 EAS exome AF: 0.00293

Gnomad4 SAS exome AF: 0.0428

Gnomad4 FIN exome AF: 0.0220

Gnomad4 NFE exome AF: 0.0277

Gnomad4 OTH exome AF: 0.0293

GnomAD4 genome AF: 0.0229 AC: 3483 AN: 152288 Hom.: 57 Cov.: 33 AF XY: 0.0228 AC XY: 1698 AN XY: 74456

Gnomad4 AFR AF: 0.00601

Gnomad4 AMR AF: 0.0273

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.00482

Gnomad4 SAS AF: 0.0465

Gnomad4 FIN AF: 0.0178

Gnomad4 NFE AF: 0.0315

Gnomad4 OTH AF: 0.0302

Alfa AF: 0.0315 Hom.: 117

Bravo AF: 0.0214

Asia WGS AF: 0.0470 AC: 165 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Dec 28, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 5A Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.3
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs118000312; hg19: chr8-65508862;