11-71435840-C-G

Variant names:

• chr11-71435840-C-G
• rs138659167
• NM_001360.3:c.964-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001360.3(DHCR7):​c.964-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00745 in 1,599,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000321549: RT-PCR and RNA analysis revealed c.964-1 G>C leads to the use of an alternative splice acceptor site upstream of the native intron 8 splice site, which results in insertion of intronic sequence, a shift in reading frame, and a premature stop of translation (PMID:9653161, 37301908)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0042 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0078 (0 hom.)
• Consequence: DHCR7 NM_001360.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:58 O:2
• Conservation: PhyloP100: 6.89
• Publications: 61 publications found

Genes affected

DHCR7 (HGNC:2860): (7-dehydrocholesterol reductase) This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. This gene is ubiquitously expressed and its transmembrane protein localizes to the endoplasmic reticulum membrane and nuclear outer membrane. Mutations in this gene cause Smith-Lemli-Opitz syndrome (SLOS); a syndrome that is metabolically characterized by reduced serum cholesterol levels and elevated serum 7-dehydrocholesterol levels and phenotypically characterized by cognitive disability, facial dysmorphism, syndactyly of second and third toes, and holoprosencephaly in severe cases to minimal physical abnormalities and near-normal intelligence in mild cases. Alternative splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Aug 2009]

DHCR7 Gene-Disease associations (from GenCC):

• Smith-Lemli-Opitz syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, ClinGen, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000321549: RT-PCR and RNA analysis revealed c.964-1 G>C leads to the use of an alternative splice acceptor site upstream of the native intron 8 splice site, which results in insertion of intronic sequence, a shift in reading frame, and a premature stop of translation (PMID: 9653161, 37301908); SCV000613096: RT-PCR study showed that disruption of this splice site led to a premature stop codon (PMID:9653161).; SCV001550205: Functional analysis has confirmed this aberrant splicing prediction and has revealed the use of an alternative splice acceptor site that produces a shifted reading frame and premature stop codon (Fitzky_1998_PMID:965316). Another functional study suggests that the c.964-1G>C variant disrupts SMO cilia localization and SHH pathway activation due to reduced cholesterol biosynthesis and reduced levels of the DHCR7 transcript (Blassberg_2016_PMID:26685159).; SCV000373914: Functional analysis of the variant using RT-PCR in patient skin fibroblasts demonstrated that the variant causes aberrant mRNA splicing and insertion of 134 bp between exons 8 and 9 resulting in a frameshift that prematurely truncates the protein. The insertion occurs in a region strongly conserved among sterol reductases (PMID: 9683613).; SCV000630077: Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a new termination codon (PMID: 9653161).; SCV000711716: Functional studies using RT-PCR of patient mRNA isolated from fibroblasts show that that this variant leads to the use of an alternative splice acceptor in intron 8, which results in the insertion of 134 bp of intronic sequence, and ultimately a frameshift and premature termination with >10% of the protein affected (Fitzky 1998 PMID: 9653161).; SCV001142422: Functional analysis of the variant using RT-PCR in patient with skin fibroblasts demonstrated that the variant causes aberrant mRNA splicing and insertion of 134 bp resulting in a frameshift that prematurely truncates the protein. The insertion occurs in a region strongly conserved among sterol reductases (PMID: 9683613).; SCV001157268: Functional studies from patient mRNA show an insertion of 134 nucleotides between exons 8 and 9, leading to a premature termination codon (Fitzky 1998).; SCV002073776: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 15805162) - PS3_moderate."; SCV002767070: RNA studies have shown this variant results in a truncated protein with less than 1/3 of the protein affected (PMID: 9653161);; SCV004046609: "In vitro functional studies showed that the variant causes aberrant mRNA splicing resulting in insertion of 134 nucleotides which alters the wild type translational reading frame and introduces a premature translation termination codon." PMID:9653161; SCV005397650: Splicing studies demonstrate that this variant causes alternative splicing which incorporates a frameshifting 134-bp insertion in the mRNA transcript (PMID: 10677299, 9683613).; SCV005900461: It is observed to cause cryptic acceptor site activation in RNA assays, resulting in an out-of-frame deletion that is expected to escape nonsense-mediated decay and truncate a critical functional domain (PMID: 9653161).; SCV000848264: Analysis of cDNA isolated from fibroblasts of a compound heterozygous individual with this alteration demonstrated the use of an alternative splice acceptor site, leading to a transcript with a shift in reading frame and a premature stop codon (Fitzky, 1998).; SCV004110145: RT-PCR studies have shown that the c.964-1G>C variant results in the use of an alternative splice acceptor site, resulting in the insertion of 134 bp of intronic DNA sequence and subsequent premature termination (Fitzky et al. 1998. PubMed ID: 9653161).
• PM2: Variant has high frequency in the NFE (0.0092) population. However there is too low homozygotes in high coverage region: (expected more than 22, got 0).
• PP5: Variant 11-71435840-C-G is Pathogenic according to our data. Variant chr11-71435840-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 93725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360.3. 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
	DHCR7	NM_001360.3	MANE Select	c.964-1G>C		splice_acceptor intron	N/A	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425112.1		c.1097G>C	p.Arg366Thr	missense	Exon 9 of 9	NP_001412041.1
	DHCR7	NM_001425116.1		c.1001G>C	p.Arg334Thr	missense	Exon 9 of 9	NP_001412045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.964-1G>C		splice_acceptor intron	N/A	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.964-1G>C		splice_acceptor intron	N/A	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.379-1G>C		splice_acceptor intron	N/A	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes AF: 0.00425 AC: 647 AN: 152210 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00683

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00386 AC: 890 AN: 230702 AF XY: 0.00392

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00154

Gnomad NFE exome AF: 0.00611

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00778 AC: 11267 AN: 1447632 Hom.: 0 Cov.: 36 AF XY: 0.00740 AC XY: 5318 AN XY: 718890

African (AFR) AF: 0.00126 AC: 42 AN: 33336

American (AMR) AF: 0.00187 AC: 83 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 313 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85896

European-Finnish (FIN) AF: 0.00158 AC: 74 AN: 46858

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.00935 AC: 10345 AN: 1106138

Other (OTH) AF: 0.00663 AC: 397 AN: 59896

GnomAD4 genome AF: 0.00425 AC: 647 AN: 152328 Hom.: 0 Cov.: 35 AF XY: 0.00365 AC XY: 272 AN XY: 74476

African (AFR) AF: 0.00171 AC: 71 AN: 41588

American (AMR) AF: 0.00229 AC: 35 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00684 AC: 465 AN: 68030

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00439

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00367 AC: 16

ESP6500EA AF: 0.00635 AC: 54

ExAC AF: 0.00343 AC: 414

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
41	-	-	Smith-Lemli-Opitz syndrome (43)
13	-	-	not provided (13)
2	-	-	See cases (2)
1	-	-	DHCR7-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		6.9
ClinPred		0.024	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: -31
DS_AL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs138659167; hg19: chr11-71146886; COSMIC: COSV106107975; COSMIC: COSV106107975;