Genetic Variant NM_001360.3:c.1228G>A (chr11-71435575-C-T) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3PM1PM5PP3_StrongPP5_Very_Strong

The NM_001360.3(DHCR7):c.1228G>A(p.Gly410Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,610,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000697851: Cell-based functional studies have been performed that revealed a severe reduction in protein expression and enzyme activity due to the variant (Fitzky_PNAS_1998" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G410R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 6.89

Publications

25 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: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women's Health

DHCR7 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001360.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000697851: Cell-based functional studies have been performed that revealed a severe reduction in protein expression and enzyme activity due to the variant (Fitzky_PNAS_1998; Shim_BBRC_2004).; SCV000832368: Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9653161).; SCV000564934: Expression studies in a human cell line found that G410S reduced DHCR7 protein expression by greater than 90% compared to wild-type (Fitzky et al., 1998);; SCV000850897: In two separate functional studies, this alteration was shown to reduce DHCR7 protein expression and enzymatic activity (Fitzky, 1998; Shim, 2004).

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001360.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-71435575-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1457187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 11-71435575-C-T is Pathogenic according to our data. Variant chr11-71435575-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 21272.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.1228G>A	p.Gly410Ser	missense	Exon 9 of 9	NP_001351.2	A0A024R5F7
DHCR7	NM_001425107.1		c.1279G>A	p.Gly427Ser	missense	Exon 10 of 10	NP_001412036.1	A0A804HI25
DHCR7	NM_001425108.1		c.1264G>A	p.Gly422Ser	missense	Exon 9 of 9	NP_001412037.1	A0A804HJQ7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.1228G>A	p.Gly410Ser	missense	Exon 9 of 9	ENSP00000347717.4	Q9UBM7
DHCR7	ENST00000407721.6	TSL:1	c.1228G>A	p.Gly410Ser	missense	Exon 9 of 9	ENSP00000384739.2	Q9UBM7
DHCR7	ENST00000685320.1		c.643G>A	p.Gly215Ser	missense	Exon 8 of 8	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000731

AC:

AN:

246180

AF XY:

0.0000447

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000448

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000343

AC:

AN:

1458636

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

725740

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.000246

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50474

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1111842

Other (OTH)

AF:

0.0000166

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.000196

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

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:

0.0000511

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Smith-Lemli-Opitz syndrome (10)

not provided (5)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

PhyloP100

6.9

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.95

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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.

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