Genetic Variant NM_001360.3:c.1341C>T (chr11-71435462-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001360.3(DHCR7):c.1341C>T(p.Asp447Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,612,632 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 19 hom. )

Consequence

DHCR7
NM_001360.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.0200

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 11-71435462-G-A is Benign according to our data. Variant chr11-71435462-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.02 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00228 (3331/1460280) while in subpopulation MID AF = 0.0218 (126/5768). AF 95% confidence interval is 0.0187. There are 19 homozygotes in GnomAdExome4. There are 1740 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.1341C>T	p.Asp447Asp	synonymous	Exon 9 of 9	NP_001351.2	A0A024R5F7
DHCR7	NM_001425107.1		c.1392C>T	p.Asp464Asp	synonymous	Exon 10 of 10	NP_001412036.1	A0A804HI25
DHCR7	NM_001425108.1		c.1377C>T	p.Asp459Asp	synonymous	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.1341C>T	p.Asp447Asp	synonymous	Exon 9 of 9	ENSP00000347717.4	Q9UBM7
DHCR7	ENST00000407721.6	TSL:1	c.1341C>T	p.Asp447Asp	synonymous	Exon 9 of 9	ENSP00000384739.2	Q9UBM7
DHCR7	ENST00000685320.1		c.756C>T	p.Asp252Asp	synonymous	Exon 8 of 8	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.00307

AC:

467

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00549

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00393

AC:

978

AN:

248946

AF XY:

0.00376

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.0360

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00203

Gnomad OTH exome

AF:

0.00672

GnomAD4 exome

AF:

0.00228

AC:

3331

AN:

1460280

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1740

AN XY:

726518

show subpopulations

African (AFR)

AF:

0.00367

AC:

123

AN:

33476

American (AMR)

AF:

0.00555

AC:

248

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

848

AN:

26116

East Asian (EAS)

AF:

0.000202

AC:

AN:

39696

South Asian (SAS)

AF:

0.00342

AC:

295

AN:

86258

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51922

Middle Eastern (MID)

AF:

0.0218

AC:

126

AN:

5768

European-Non Finnish (NFE)

AF:

0.00122

AC:

1358

AN:

1111946

Other (OTH)

AF:

0.00537

AC:

324

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

259

518

777

1036

1295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00307

AC:

467

AN:

152352

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

226

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00296

AC:

123

AN:

41586

American (AMR)

AF:

0.00549

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

122

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00331

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

68034

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00458

Hom.:

Bravo

AF:

0.00357

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00371

EpiControl

AF:

0.00273

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Smith-Lemli-Opitz syndrome (4)

not specified (3)

DHCR7-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.5

(source)

DANN

Benign

0.77

PhyloP100

0.020

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(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

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