11-71441420-T-G

Position:

• chr11-71441420-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001360.3(DHCR7):​c.433A>C​(p.Ile145Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I145T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.64

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71441419-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 11-71441420-T-G is Pathogenic according to our data. Variant chr11-71441420-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558625.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr11-71441420-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.433A>C	p.Ile145Leu	missense_variant	6/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.433A>C	p.Ile145Leu	missense_variant	6/9
DHCR7	XM_011544777.3	c.433A>C	p.Ile145Leu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.433A>C	p.Ile145Leu	missense_variant	6/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461172 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 29, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DHCR7 protein function. ClinVar contains an entry for this variant (Variation ID: 558625). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 15954111, 20556518). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 145 of the DHCR7 protein (p.Ile145Leu). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.433A>C;p.(Ile145Leu) missense change has been observed in affected individual(s) (PMID: 20556518; 15954111; 30925529) - PS4. This variant is not present in population databases:rs1555146475, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Ile145Leu) was detected in trans with a Pathogenic variant (PMID: 20556518; 15954111; 30925529) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 30925529) - PP1. In summary, the currently available evidence indicates that the variant is Pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.86	D;D;.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.2	L;L;.;.
MutationTaster	Benign	0.88	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.022	D;D;D;T
Sift4G	Uncertain	0.036	D;D;.;.
Polyphen		0.049	B;B;.;.
Vest4		0.40
MutPred		0.80		Loss of methylation at K142 (P = 0.0651);Loss of methylation at K142 (P = 0.0651);.;Loss of methylation at K142 (P = 0.0651);
MVP		0.74
MPC		0.14
ClinPred		0.13	T
GERP RS		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555146475; hg19: chr11-71152466;