rs77809319

chr22-41900991-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004599.4(SREBF2):c.2907+493A>G variant causes a intron change. The variant allele was found at a frequency of 0.000279 in 531,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06

Genes affected

SREBF2 (HGNC:11290): (sterol regulatory element binding transcription factor 2) This gene encodes a member of the a ubiquitously expressed transcription factor that controls cholesterol homeostasis by regulating transcription of sterol-regulated genes. The encoded protein contains a basic helix-loop-helix-leucine zipper (bHLH-Zip) domain and binds the sterol regulatory element 1 motif. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

MIR33A (HGNC:31634): (microRNA 33a) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BS2: High AC in GnomAd at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SREBF2	NM_004599.4	c.2907+493A>G		intron_variant		ENST00000361204.9
MIR33A	NR_029507.1	n.48A>G		non_coding_transcript_exon_variant	1/1
SREBF2	XM_011530347.3	c.2532+493A>G		intron_variant
SREBF2	NR_103834.2	n.3593+493A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SREBF2	ENST00000361204.9	c.2907+493A>G		intron_variant		1	NM_004599.4	P3
MIR33A	ENST00000385197.1	n.48A>G		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000400 AC: 98 AN: 245238 Hom.: 0 AF XY: 0.000399 AC XY: 53 AN XY: 132852

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000910

Gnomad EAS exome AF: 0.00311

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000261

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000245 AC: 93 AN: 378986 Hom.: 0 Cov.: 0 AF XY: 0.000218 AC XY: 47 AN XY: 215784

Gnomad4 AFR exome AF: 0.0000953

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000943

Gnomad4 EAS exome AF: 0.00235

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.000240

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74420

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.000366

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	14
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs77809319; hg19: chr22-42296995;