rs2297508

Positions:

• chr17-17812003-C-G
• chr17-17812003-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004176.5(SREBF1):​c.*619G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 437,516 control chromosomes in the GnomAD database, including 68,804 homozygotes. 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 0.57 (25617 hom., cov: 33)
  • Exomes 𝑓: 0.53 (43187 hom.)
• Consequence: SREBF1 NM_004176.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240

Genes affected

SREBF1 (HGNC:11289): (sterol regulatory element binding transcription factor 1) This gene encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor that binds to the sterol regulatory element-1 (SRE1), which is a motif that is found in the promoter of the low density lipoprotein receptor gene and other genes involved in sterol biosynthesis. The encoded protein is synthesized as a precursor that is initially attached to the nuclear membrane and endoplasmic reticulum. Following cleavage, the mature protein translocates to the nucleus and activates transcription. This cleaveage is inhibited by sterols. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Alternative promoter usage and splicing result in multiple transcript variants, including SREBP-1a and SREBP-1c, which correspond to RefSeq transcript variants 2 and 3, respectively. [provided by RefSeq, Nov 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SREBF1	NM_004176.5	c.*619G>C		3_prime_UTR_variant	19/19	ENST00000261646.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SREBF1	ENST00000261646.11	c.*619G>C		3_prime_UTR_variant	19/19	1	NM_004176.5	P4
SREBF1	ENST00000395757.6	c.3156G>C	p.Gly1052=	synonymous_variant	18/19	2
SREBF1	ENST00000485080.6	c.*34G>C		3_prime_UTR_variant, NMD_transcript_variant	3/5	5
SREBF1	ENST00000578469.1	c.*34G>C		3_prime_UTR_variant, NMD_transcript_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86684 AN: 151876 Hom.: 25589 Cov.: 33

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.634

Gnomad OTH AF: 0.575

GnomAD3 exomes AF: 0.498 AC: 59899 AN: 120346 Hom.: 16492 AF XY: 0.493 AC XY: 32640 AN XY: 66186

Gnomad AFR exome AF: 0.570

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.317

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.631

Gnomad OTH exome AF: 0.530

GnomAD4 exome AF: 0.529 AC: 150938 AN: 285520 Hom.: 43187 Cov.: 0 AF XY: 0.509 AC XY: 83622 AN XY: 164168

Gnomad4 AFR exome AF: 0.574

Gnomad4 AMR exome AF: 0.390

Gnomad4 ASJ exome AF: 0.582

Gnomad4 EAS exome AF: 0.152

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.602

Gnomad4 NFE exome AF: 0.630

Gnomad4 OTH exome AF: 0.574

GnomAD4 genome AF: 0.571 AC: 86772 AN: 151996 Hom.: 25617 Cov.: 33 AF XY: 0.559 AC XY: 41497 AN XY: 74274

Gnomad4 AFR AF: 0.580

Gnomad4 AMR AF: 0.476

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.154

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.634

Gnomad4 OTH AF: 0.577

Alfa AF: 0.542 Hom.: 3164

Bravo AF: 0.564

Asia WGS AF: 0.304 AC: 1059 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.6
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2297508; hg19: chr17-17715317; COSMIC: COSV55397229;