rs1044482

Variant names:

• chr11-71444125-C-A
• rs1044482
• NM_001360.3:c.189G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-71444125-C-A
• chr11-71444125-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001360.3(DHCR7):​c.189G>T​(p.Gln63His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. Q63Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07
• Publications: 29 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 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

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.189G>T	p.Gln63His	missense	Exon 4 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425107.1		c.189G>T	p.Gln63His	missense	Exon 4 of 10	NP_001412036.1	A0A804HI25
	DHCR7	NM_001425108.1		c.189G>T	p.Gln63His	missense	Exon 4 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.189G>T	p.Gln63His	missense	Exon 4 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.189G>T	p.Gln63His	missense	Exon 4 of 9	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.-333-64G>T		intron	N/A	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458206 Hom.: 0 Cov.: 53 AF XY: 0.00 AC XY: 0 AN XY: 725072

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110412

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.0	L
PhyloP100		3.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.51	N
REVEL	Uncertain	0.55
Sift	Benign	0.58	T
Sift4G	Benign	0.42	T
Polyphen		0.018	B
Vest4		0.73
MutPred		0.47		Gain of glycosylation at S65 (P = 0.2623)
MVP		0.85
MPC		0.15
ClinPred		0.13	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.68
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1044482; hg19: chr11-71155171;