8-64596113-T-C

Position:

• chr8-64596113-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_004820.5(CYP7B1):​c.*529A>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 0.0367 in 162,290 control chromosomes in the GnomAD database, including 356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (355 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (1 hom.)
• Consequence: CYP7B1 NM_004820.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.14

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-64596113-T-C is Benign according to our data. Variant chr8-64596113-T-C is described in ClinVar as [Benign]. Clinvar id is 363574.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP7B1	NM_004820.5	c.*529A>G		3_prime_UTR_variant	6/6	ENST00000310193.4	NP_004811.1
CYP7B1	XM_017014002.2	c.*529A>G		3_prime_UTR_variant	7/7		XP_016869491.1
CYP7B1	NM_001324112.2	c.1234-6269A>G		intron_variant			NP_001311041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP7B1	ENST00000310193.4	c.*529A>G		3_prime_UTR_variant	6/6	1	NM_004820.5	ENSP00000310721	P1
CYP7B1	ENST00000523954.1	n.508-6269A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5914 AN: 152168 Hom.: 355 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0373

GnomAD4 exome AF: 0.00410 AC: 41 AN: 10004 Hom.: 1 Cov.: 0 AF XY: 0.00219 AC XY: 14 AN XY: 6388

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00323

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000603

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0388 AC: 5916 AN: 152286 Hom.: 355 Cov.: 32 AF XY: 0.0376 AC XY: 2802 AN XY: 74466

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0122 Hom.: 52

Bravo AF: 0.0442

Asia WGS AF: 0.0130 AC: 45 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 5A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.69

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113473170; hg19: chr8-65508670;