rs12422045

Variant names:

• chr11-71443774-G-A
• rs12422045
• NM_001360.3:c.321+219C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-71443774-G-A
• chr11-71443774-G-C
• chr11-71443774-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001360.3(DHCR7):​c.321+219C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 152,060 control chromosomes in the GnomAD database, including 25,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.53 (25055 hom., cov: 32)
• Consequence: DHCR7 NM_001360.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.50
• Publications: 15 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: Orphanet, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-71443774-G-A is Benign according to our data. Variant chr11-71443774-G-A is described in ClinVar as Benign. ClinVar VariationId is 679281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.321+219C>T		intron_variant	Intron 4 of 8	ENST00000355527.8	NP_001351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.321+219C>T		intron_variant	Intron 4 of 8	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-265+219C>T		intron_variant	Intron 3 of 7			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80447 AN: 151942 Hom.: 25055 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.517

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.529 AC: 80459 AN: 152060 Hom.: 25055 Cov.: 32 AF XY: 0.515 AC XY: 38259 AN XY: 74330

African (AFR) AF: 0.235 AC: 9740 AN: 41490

American (AMR) AF: 0.519 AC: 7926 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2139 AN: 3470

East Asian (EAS) AF: 0.364 AC: 1877 AN: 5152

South Asian (SAS) AF: 0.203 AC: 978 AN: 4816

European-Finnish (FIN) AF: 0.570 AC: 6020 AN: 10570

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49946 AN: 67962

Other (OTH) AF: 0.511 AC: 1080 AN: 2112

Alfa AF: 0.533 Hom.: 7329

Bravo AF: 0.523

Asia WGS AF: 0.251 AC: 878 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Smith-Lemli-Opitz syndrome Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.037
DANN	Benign	0.47
PhyloP100		-4.5
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs12422045; hg19: chr11-71154820; COSMIC: COSV107444258; COSMIC: COSV107444258;