11-71435840-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_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 (★★).

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:58O:2

Conservation

PhyloP100: 6.89

Publications

59 publications found

Variant links:

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

DHCR7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

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

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

Gene	Transcript	Tags	HGVSc	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.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00740

AC XY:

5318

AN XY:

718890

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

33336

American (AMR)

AF:

0.00187

AC:

AN:

44420

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

313

AN:

25882

East Asian (EAS)

AF:

0.00

AC:

AN:

39462

South Asian (SAS)

AF:

0.000128

AC:

AN:

85896

European-Finnish (FIN)

AF:

0.00158

AC:

AN:

46858

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00935

AC:

10345

AN:

1106138

Other (OTH)

AF:

0.00663

AC:

397

AN:

59896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

549

1098

1646

2195

2744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

440

880

1320

1760

2200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00425

AC:

647

AN:

152328

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41588

American (AMR)

AF:

0.00229

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00684

AC:

465

AN:

68030

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00197

Hom.:

Bravo

AF:

0.00439

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00367

AC:

ESP6500EA

AF:

0.00635

AC:

ExAC

AF:

0.00343

AC:

414

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Smith-Lemli-Opitz syndrome (43)

not provided (13)

See cases (2)

DHCR7-related disorder (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

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.97

PhyloP100

6.9

ClinPred

0.024

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over