rs11868035

Positions:

• chr17-17811787-G-A

Variant summary

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

The NM_004176.5(SREBF1):​c.*835C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 453,984 control chromosomes in the GnomAD database, including 41,137 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 0.34 (10053 hom., cov: 31)
  • Exomes 𝑓: 0.42 (31084 hom.)
• Consequence: SREBF1 NM_004176.5 3_prime_UTR
• Scores: Splicing: ADA: 0.00006245
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SREBF1	NM_004176.5	c.*835C>T		3_prime_UTR_variant	19/19	ENST00000261646.11	NP_004167.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SREBF1	ENST00000261646.11	c.*835C>T		3_prime_UTR_variant	19/19	1	NM_004176.5	ENSP00000261646	P4
SREBF1	ENST00000395757.6	c.3187-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000379106
SREBF1	ENST00000485080.6	c.*65-57C>T		intron_variant, NMD_transcript_variant		5		ENSP00000466643
SREBF1	ENST00000578469.1	c.*65-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3		ENSP00000465747

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51451 AN: 151954 Hom.: 10056 Cov.: 31

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.330

GnomAD3 exomes AF: 0.453 AC: 60745 AN: 134044 Hom.: 16216 AF XY: 0.461 AC XY: 33634 AN XY: 72996

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.853

Gnomad SAS exome AF: 0.666

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.419 AC: 126474 AN: 301912 Hom.: 31084 Cov.: 0 AF XY: 0.441 AC XY: 75994 AN XY: 172156

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.560

Gnomad4 ASJ exome AF: 0.336

Gnomad4 EAS exome AF: 0.846

Gnomad4 SAS exome AF: 0.666

Gnomad4 FIN exome AF: 0.324

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.363

GnomAD4 genome AF: 0.338 AC: 51459 AN: 152072 Hom.: 10053 Cov.: 31 AF XY: 0.352 AC XY: 26133 AN XY: 74332

Gnomad4 AFR AF: 0.256

Gnomad4 AMR AF: 0.446

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.845

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.328

Alfa AF: 0.334 Hom.: 10952

Bravo AF: 0.342

Asia WGS AF: 0.677 AC: 2351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.5
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs11868035; hg19: chr17-17715101;