8-64615112-C-T

Position:

• chr8-64615112-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004820.5(CYP7B1):​c.971G>A​(p.Arg324His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,613,552 control chromosomes in the GnomAD database, including 1,319 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (91 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1228 hom.)
• Consequence: CYP7B1 NM_004820.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.781

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002134025).
• BP6: Variant 8-64615112-C-T is Benign according to our data. Variant chr8-64615112-C-T is described in ClinVar as [Benign]. Clinvar id is 363582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-64615112-C-T is described in Lovd as [Likely_benign]. Variant chr8-64615112-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP7B1	NM_004820.5	c.971G>A	p.Arg324His	missense_variant	4/6	ENST00000310193.4	NP_004811.1
CYP7B1	NM_001324112.2	c.971G>A	p.Arg324His	missense_variant	4/7		NP_001311041.1
CYP7B1	XM_017014002.2	c.1037G>A	p.Arg346His	missense_variant	5/7		XP_016869491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP7B1	ENST00000310193.4	c.971G>A	p.Arg324His	missense_variant	4/6	1	NM_004820.5	ENSP00000310721.3
CYP7B1	ENST00000523954.1	n.245G>A		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4178 AN: 152016 Hom.: 91 Cov.: 32

Gnomad AFR AF: 0.00676

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0903

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0302

GnomAD3 exomes AF: 0.0343 AC: 8608 AN: 251132 Hom.: 208 AF XY: 0.0371 AC XY: 5039 AN XY: 135718

Gnomad AFR exome AF: 0.00578

Gnomad AMR exome AF: 0.0212

Gnomad ASJ exome AF: 0.0973

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0438

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.0414

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0377 AC: 55056 AN: 1461418 Hom.: 1228 Cov.: 32 AF XY: 0.0382 AC XY: 27789 AN XY: 727016

Gnomad4 AFR exome AF: 0.00550

Gnomad4 AMR exome AF: 0.0218

Gnomad4 ASJ exome AF: 0.0982

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0453

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0383

GnomAD4 genome AF: 0.0275 AC: 4180 AN: 152134 Hom.: 91 Cov.: 32 AF XY: 0.0260 AC XY: 1933 AN XY: 74368

Gnomad4 AFR AF: 0.00674

Gnomad4 AMR AF: 0.0258

Gnomad4 ASJ AF: 0.0903

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0407

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0393

Gnomad4 OTH AF: 0.0323

Alfa AF: 0.0392 Hom.: 227

Bravo AF: 0.0271

TwinsUK AF: 0.0418 AC: 155

ALSPAC AF: 0.0337 AC: 130

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0400 AC: 344

ExAC AF: 0.0334 AC: 4050

Asia WGS AF: 0.0250 AC: 85 AN: 3478

EpiCase AF: 0.0440

EpiControl AF: 0.0490

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 11, 2021

- -

Hereditary spastic paraplegia 5A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.56
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.83	N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.13
Sift	Benign	0.71	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.092
MPC		0.095
ClinPred		0.0036	T
GERP RS		-4.4
Varity_R		0.029
gMVP		0.15

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: rs59035258; hg19: chr8-65527669; COSMIC: COSV100041529;