NM_001360.3:c.1022T>C

Variant names:

• chr11-71435781-A-G
• rs1317526744
• NM_001360.3:c.1022T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001360.3(DHCR7):​c.1022T>C​(p.Leu341Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 1,456,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 8.12
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-71435781-A-G is Pathogenic according to our data. Variant chr11-71435781-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 551380.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	NM_001360.3	MANE Select	c.1022T>C	p.Leu341Pro	missense	Exon 9 of 9	NP_001351.2
	DHCR7	NM_001425107.1		c.1073T>C	p.Leu358Pro	missense	Exon 10 of 10	NP_001412036.1
	DHCR7	NM_001425108.1		c.1058T>C	p.Leu353Pro	missense	Exon 9 of 9	NP_001412037.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.1022T>C	p.Leu341Pro	missense	Exon 9 of 9	ENSP00000347717.4
	DHCR7	ENST00000407721.6	TSL:1	c.1022T>C	p.Leu341Pro	missense	Exon 9 of 9	ENSP00000384739.2
	DHCR7	ENST00000685320.1		c.437T>C	p.Leu146Pro	missense	Exon 8 of 8	ENSP00000509319.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247380 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1456786 Hom.: 0 Cov.: 37 AF XY: 0.0000111 AC XY: 8 AN XY: 723910

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1108834

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome Cov.: 35

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Smith-Lemli-Opitz syndrome (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.16	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		8.1
PROVEAN	Benign	1.6	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
MutPred		0.33		Gain of MoRF binding (P = 0.0108)
MVP		0.88
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.97
Mutation Taster		=2/98	disease causing

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: rs1317526744; hg19: chr11-71146827;