8-64615112-C-T

Variant names:

• chr8-64615112-C-T
• rs59035258
• NM_004820.5:c.971G>A
• CYP7B1 p.Arg324His

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324G) has been classified as Uncertain significance.

• 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:9
• Conservation: PhyloP100: 0.781
• Publications: 19 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• hereditary spastic paraplegia 5A

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 363582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

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.971G>A	p.Arg324His	missense	Exon 4 of 6	NP_004811.1	O75881
	CYP7B1	NM_001324112.2		c.971G>A	p.Arg324His	missense	Exon 4 of 7	NP_001311041.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7B1	ENST00000310193.4	TSL:1 MANE Select	c.971G>A	p.Arg324His	missense	Exon 4 of 6	ENSP00000310721.3	O75881
	CYP7B1	ENST00000864436.1		c.1124G>A	p.Arg375His	missense	Exon 6 of 8	ENSP00000534495.1
	CYP7B1	ENST00000864435.1		c.971G>A	p.Arg324His	missense	Exon 5 of 7	ENSP00000534494.1

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

GnomAD2 exomes AF: 0.0343 AC: 8608 AN: 251132 AF XY: 0.0371

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 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

African (AFR) AF: 0.00550 AC: 184 AN: 33454

American (AMR) AF: 0.0218 AC: 975 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0982 AC: 2566 AN: 26122

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0453 AC: 3911 AN: 86246

European-Finnish (FIN) AF: 0.0236 AC: 1258 AN: 53376

Middle Eastern (MID) AF: 0.0626 AC: 361 AN: 5768

European-Non Finnish (NFE) AF: 0.0391 AC: 43488 AN: 1111742

Other (OTH) AF: 0.0383 AC: 2311 AN: 60358

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

African (AFR) AF: 0.00674 AC: 280 AN: 41516

American (AMR) AF: 0.0258 AC: 394 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0903 AC: 313 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0407 AC: 196 AN: 4820

European-Finnish (FIN) AF: 0.0203 AC: 215 AN: 10592

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0393 AC: 2669 AN: 67988

Other (OTH) AF: 0.0323 AC: 68 AN: 2108

Alfa AF: 0.0376 Hom.: 442

Bravo AF: 0.0271

Asia WGS AF: 0.0250 AC: 85 AN: 3478

EpiCase AF: 0.0440

EpiControl AF: 0.0490

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 5A (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.78
PrimateAI	Benign	0.19	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.13
Sift	Benign	0.71	T
Sift4G	Benign	1.0	T
Varity_R		0.029
gMVP		0.15
Mutation Taster		=94/6	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs59035258;

hg19: chr8-65527669;

COSMIC: COSV100041529;