rs140748737

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-71444219-C-A
• chr11-71444219-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001360.3(DHCR7):​c.99-4G>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 0.00000422 in 1,423,404 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: DHCR7 NM_001360.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002657
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20
• Publications: 0 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women's Health

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18681628).
• BP6: Variant 11-71444219-C-A is Benign according to our data. Variant chr11-71444219-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1987103.Status of the report is criteria_provided_single_submitter, 1 stars.

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>T		splice_region intron	N/A	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425117.1		c.-80G>T		5_prime_UTR	Exon 4 of 9	NP_001412046.1	E9PM00
	DHCR7	NM_001425107.1		c.99-4G>T		splice_region intron	N/A	NP_001412036.1	A0A804HI25

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.99-4G>T		splice_region intron	N/A	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.99-4G>T		splice_region intron	N/A	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.-333-158G>T		intron	N/A	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1423404 Hom.: 0 Cov.: 34 AF XY: 0.00000568 AC XY: 4 AN XY: 704406

African (AFR) AF: 0.0000305 AC: 1 AN: 32766

American (AMR) AF: 0.0000256 AC: 1 AN: 38988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.00 AC: 0 AN: 37816

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1091500

Other (OTH) AF: 0.0000170 AC: 1 AN: 58992

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Smith-Lemli-Opitz syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.64
DANN	Benign	0.78
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.12	T
PhyloP100		-1.2
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.18
Sift	Benign	0.17	T
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	0.00027
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs140748737;

hg19: chr11-71155265;