11-71441415-A-G

Variant names:

• chr11-71441415-A-G
• rs949177
• NM_001360.3:c.438T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001360.3(DHCR7):​c.438T>C​(p.Asn146Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 1,613,484 control chromosomes in the GnomAD database, including 693,364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (61265 hom., cov: 33)
  • Exomes 𝑓: 0.93 (632099 hom.)
• Consequence: DHCR7 NM_001360.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.0240
• Publications: 26 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-71441415-A-G is Benign according to our data. Variant chr11-71441415-A-G is described in ClinVar as Benign. ClinVar VariationId is 93719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.024 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

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.438T>C	p.Asn146Asn	synonymous	Exon 6 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425107.1		c.438T>C	p.Asn146Asn	synonymous	Exon 6 of 10	NP_001412036.1	A0A804HI25
	DHCR7	NM_001425108.1		c.474T>C	p.Asn158Asn	synonymous	Exon 6 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.438T>C	p.Asn146Asn	synonymous	Exon 6 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.438T>C	p.Asn146Asn	synonymous	Exon 6 of 9	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.-148T>C		5_prime_UTR	Exon 5 of 8	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes AF: 0.894 AC: 136007 AN: 152112 Hom.: 61231 Cov.: 33

Gnomad AFR AF: 0.832

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.846

Gnomad ASJ AF: 0.839

Gnomad EAS AF: 0.842

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.956

Gnomad OTH AF: 0.896

GnomAD2 exomes AF: 0.871 AC: 216454 AN: 248488 AF XY: 0.869

Gnomad AFR exome AF: 0.831

Gnomad AMR exome AF: 0.771

Gnomad ASJ exome AF: 0.849

Gnomad EAS exome AF: 0.848

Gnomad FIN exome AF: 0.946

Gnomad NFE exome AF: 0.950

Gnomad OTH exome AF: 0.889

GnomAD4 exome AF: 0.927 AC: 1354189 AN: 1461254 Hom.: 632099 Cov.: 49 AF XY: 0.920 AC XY: 668971 AN XY: 726900

African (AFR) AF: 0.822 AC: 27503 AN: 33462

American (AMR) AF: 0.778 AC: 34690 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 22172 AN: 26124

East Asian (EAS) AF: 0.868 AC: 34424 AN: 39674

South Asian (SAS) AF: 0.688 AC: 59324 AN: 86200

European-Finnish (FIN) AF: 0.945 AC: 50459 AN: 53386

Middle Eastern (MID) AF: 0.801 AC: 4615 AN: 5764

European-Non Finnish (NFE) AF: 0.959 AC: 1066627 AN: 1111702

Other (OTH) AF: 0.901 AC: 54375 AN: 60372

GnomAD4 genome AF: 0.894 AC: 136092 AN: 152230 Hom.: 61265 Cov.: 33 AF XY: 0.890 AC XY: 66241 AN XY: 74424

African (AFR) AF: 0.832 AC: 34538 AN: 41524

American (AMR) AF: 0.845 AC: 12933 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.839 AC: 2912 AN: 3472

East Asian (EAS) AF: 0.843 AC: 4349 AN: 5160

South Asian (SAS) AF: 0.679 AC: 3271 AN: 4816

European-Finnish (FIN) AF: 0.945 AC: 10038 AN: 10618

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.956 AC: 65010 AN: 68024

Other (OTH) AF: 0.893 AC: 1885 AN: 2110

Alfa AF: 0.914 Hom.: 45930

Bravo AF: 0.885

Asia WGS AF: 0.706 AC: 2456 AN: 3478

EpiCase AF: 0.950

EpiControl AF: 0.949

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	Smith-Lemli-Opitz syndrome (9)
-	-	5	not specified (5)
-	-	2	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	0.20
DANN	Benign	0.47
PhyloP100		-0.024
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs949177; hg19: chr11-71152461; COSMIC: COSV108175199; COSMIC: COSV108175199;