rs370748173

Variant names:

• chr11-71444091-T-A
• rs370748173
• NM_001360.3:c.223A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-71444091-T-A
• chr11-71444091-T-C
• chr11-71444091-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001360.3(DHCR7):​c.223A>T​(p.Ile75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,613,504 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I75I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: -2.84
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14733475).

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.223A>T	p.Ile75Phe	missense	Exon 4 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425107.1		c.223A>T	p.Ile75Phe	missense	Exon 4 of 10	NP_001412036.1	A0A804HI25
	DHCR7	NM_001425108.1		c.223A>T	p.Ile75Phe	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.223A>T	p.Ile75Phe	missense	Exon 4 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.223A>T	p.Ile75Phe	missense	Exon 4 of 9	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.-333-30A>T		intron	N/A	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249596 AF XY: 0.000111

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000274 AC: 401 AN: 1461308 Hom.: 1 Cov.: 30 AF XY: 0.000279 AC XY: 203 AN XY: 726868

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000896 AC: 4 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86074

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000348 AC: 387 AN: 1111840

Other (OTH) AF: 0.000132 AC: 8 AN: 60378

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000273

EpiControl AF: 0.000357

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Smith-Lemli-Opitz syndrome (4)
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	0.037
DANN	Benign	0.78
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.91	L
PhyloP100		-2.8
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.45
Sift	Benign	0.21	T
Sift4G	Benign	0.30	T
Polyphen		0.23	B
Vest4		0.22
MVP		0.52
MPC		0.34
ClinPred		0.034	T
GERP RS		-9.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.60
Mutation Taster		=86/14	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: rs370748173; hg19: chr11-71155137; COSMIC: COSV62794412; COSMIC: COSV62794412;