rs1555146021

Variant names:

• chr11-71438902-T-C
• rs1555146021
• NM_001360.3:c.808A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001360.3(DHCR7):​c.808A>G​(p.Met270Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,552 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M270T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 6.97
• Publications: 0 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 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 11-71438902-T-C is Pathogenic according to our data. Variant chr11-71438902-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556307.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.808A>G	p.Met270Val	missense	Exon 7 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425107.1		c.859A>G	p.Met287Val	missense	Exon 8 of 10	NP_001412036.1	A0A804HI25
	DHCR7	NM_001425108.1		c.844A>G	p.Met282Val	missense	Exon 7 of 9	NP_001412037.1	A0A804HJQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.808A>G	p.Met270Val	missense	Exon 7 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.808A>G	p.Met270Val	missense	Exon 7 of 9	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.223A>G	p.Met75Val	missense	Exon 6 of 8	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461552 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Smith-Lemli-Opitz syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.014	D
Polyphen		0.96	D
Vest4		0.92
MutPred		0.59		Loss of catalytic residue at V266 (P = 0.0487)
MVP		0.94
MPC		0.21
ClinPred		0.93	D
GERP RS		4.5
PromoterAI		0.00070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.97
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555146021; hg19: chr11-71149948;