rs144562471

Variant names:

• chr11-71435435-G-A
• rs144562471
• NM_001360.3:c.1368C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-71435435-G-A
• chr11-71435435-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001425111.1(DHCR7):​c.1361+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,612,750 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: DHCR7 NM_001425111.1 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 0.838
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-71435435-G-A is Benign according to our data. Variant chr11-71435435-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93710.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425111.1. 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.1368C>T	p.Gly456Gly	synonymous	Exon 9 of 9	NP_001351.2
	DHCR7	NM_001425107.1		c.1419C>T	p.Gly473Gly	synonymous	Exon 10 of 10	NP_001412036.1
	DHCR7	NM_001425108.1		c.1404C>T	p.Gly468Gly	synonymous	Exon 9 of 9	NP_001412037.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.1368C>T	p.Gly456Gly	synonymous	Exon 9 of 9	ENSP00000347717.4
	DHCR7	ENST00000407721.6	TSL:1	c.1368C>T	p.Gly456Gly	synonymous	Exon 9 of 9	ENSP00000384739.2
	DHCR7	ENST00000685320.1		c.783C>T	p.Gly261Gly	synonymous	Exon 8 of 8	ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.000755 AC: 115 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000923 AC: 229 AN: 248208 AF XY: 0.00100

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000988

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.00115 AC: 1683 AN: 1460400 Hom.: 4 Cov.: 30 AF XY: 0.00113 AC XY: 820 AN XY: 726570

African (AFR) AF: 0.000209 AC: 7 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00110 AC: 95 AN: 86254

European-Finnish (FIN) AF: 0.00108 AC: 56 AN: 52004

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00134 AC: 1485 AN: 1111966

Other (OTH) AF: 0.000596 AC: 36 AN: 60382

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74494

African (AFR) AF: 0.000192 AC: 8 AN: 41592

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68032

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000844 Hom.: 1

Bravo AF: 0.000706

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	2	Smith-Lemli-Opitz syndrome (3)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.1
DANN	Benign	0.76
PhyloP100		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=97/3	polymorphism

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: rs144562471; hg19: chr11-71146481;