11-71444219-C-T

Variant names:

• chr11-71444219-C-T
• rs140748737
• NM_001360.3:c.99-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001360.3(DHCR7):​c.99-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,575,646 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (11 hom., cov: 32)
  • Exomes 𝑓: 0.012 (130 hom.)
• Consequence: DHCR7 NM_001360.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005067
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.20
• Publications: 7 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 (MetaRNN=0.00608477).
• BP6: Variant 11-71444219-C-T is Benign according to our data. Variant chr11-71444219-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00982 (1495/152270) while in subpopulation NFE AF = 0.016 (1085/68006). AF 95% confidence interval is 0.0152. There are 11 homozygotes in GnomAd4. There are 699 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	NM_001360.3	MANE Select	c.99-4G>A		splice_region intron	N/A	NP_001351.2
	DHCR7	NM_001425117.1		c.-80G>A		5_prime_UTR	Exon 4 of 9	NP_001412046.1
	DHCR7	NM_001425107.1		c.99-4G>A		splice_region intron	N/A	NP_001412036.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.99-4G>A		splice_region intron	N/A	ENSP00000347717.4
	DHCR7	ENST00000407721.6	TSL:1	c.99-4G>A		splice_region intron	N/A	ENSP00000384739.2
	DHCR7	ENST00000685320.1		c.-333-158G>A		intron	N/A	ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.00983 AC: 1495 AN: 152152 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00975 AC: 1824 AN: 187140 AF XY: 0.0102

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00446

Gnomad EAS exome AF: 0.00150

Gnomad FIN exome AF: 0.0160

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.0118 AC: 16736 AN: 1423376 Hom.: 130 Cov.: 34 AF XY: 0.0117 AC XY: 8224 AN XY: 704398

African (AFR) AF: 0.00134 AC: 44 AN: 32766

American (AMR) AF: 0.00274 AC: 107 AN: 38988

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 103 AN: 25484

East Asian (EAS) AF: 0.00936 AC: 354 AN: 37816

South Asian (SAS) AF: 0.00545 AC: 444 AN: 81526

European-Finnish (FIN) AF: 0.0182 AC: 919 AN: 50610

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5720

European-Non Finnish (NFE) AF: 0.0129 AC: 14077 AN: 1091476

Other (OTH) AF: 0.0115 AC: 679 AN: 58990

GnomAD4 genome AF: 0.00982 AC: 1495 AN: 152270 Hom.: 11 Cov.: 32 AF XY: 0.00939 AC XY: 699 AN XY: 74454

African (AFR) AF: 0.00250 AC: 104 AN: 41548

American (AMR) AF: 0.00398 AC: 61 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5176

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4824

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1085 AN: 68006

Other (OTH) AF: 0.00997 AC: 21 AN: 2106

Alfa AF: 0.0108 Hom.: 9

Bravo AF: 0.00824

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0139 AC: 119

ExAC AF: 0.00924 AC: 1106

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	Smith-Lemli-Opitz syndrome (4)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	1.2
DANN	Benign	0.80
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0061	T
MetaSVM	Uncertain	-0.19	T
PhyloP100		-1.2
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.18
Sift	Benign	0.13	T
MVP		0.84
ClinPred		0.0014	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00051
dbscSNV1_RF	Benign	0.010
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: rs140748737; hg19: chr11-71155265; COSMIC: COSV62795549; COSMIC: COSV62795549;