8-64596593-G-A

Position:

• chr8-64596593-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000310193.4(CYP7B1):​c.*49C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,517,454 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (35 hom.)
• Consequence: CYP7B1 ENST00000310193.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.741

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-64596593-G-A is Benign according to our data. Variant chr8-64596593-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 908301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.002 (304/152266) while in subpopulation EAS AF= 0.0226 (117/5188). AF 95% confidence interval is 0.0192. There are 4 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP7B1	NM_004820.5	c.*49C>T		3_prime_UTR_variant	6/6	ENST00000310193.4	NP_004811.1
CYP7B1	XM_017014002.2	c.*49C>T		3_prime_UTR_variant	7/7		XP_016869491.1
CYP7B1	NM_001324112.2	c.1234-6749C>T		intron_variant			NP_001311041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP7B1	ENST00000310193.4	c.*49C>T		3_prime_UTR_variant	6/6	1	NM_004820.5	ENSP00000310721	P1
CYP7B1	ENST00000523954.1	n.508-6749C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152148 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00556 AC: 1124 AN: 202322 Hom.: 19 AF XY: 0.00568 AC XY: 623 AN XY: 109728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0164

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000710

Gnomad OTH exome AF: 0.00192

GnomAD4 exome AF: 0.00191 AC: 2603 AN: 1365188 Hom.: 35 Cov.: 22 AF XY: 0.00226 AC XY: 1535 AN XY: 680628

Gnomad4 AFR exome AF: 0.0000976

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0185

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000713

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152266 Hom.: 4 Cov.: 33 AF XY: 0.00261 AC XY: 194 AN XY: 74458

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0226

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000952 Hom.: 2

Bravo AF: 0.00227

Asia WGS AF: 0.0140 AC: 49 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2019	- -

Hereditary spastic paraplegia 5A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.86
DANN	Benign	0.41

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: rs8192907; hg19: chr8-65509150;