rs11868035

Variant names:

• chr17-17811787-G-A
• rs11868035
• NM_004176.5:c.*835C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 118 publications found

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]

SREBF1 Gene-Disease associations (from GenCC):

• hereditary mucoepithelial dysplasia

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, PanelApp Australia
• IFAP syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SREBF1	NM_004176.5	c.*835C>T		3_prime_UTR_variant	Exon 19 of 19	ENST00000261646.11	NP_004167.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SREBF1	ENST00000261646.11	c.*835C>T		3_prime_UTR_variant	Exon 19 of 19	1	NM_004176.5	ENSP00000261646.5
SREBF1	ENST00000395757.6	c.3187-3C>T		splice_region_variant, intron_variant	Intron 18 of 18	2		ENSP00000379106.2
SREBF1	ENST00000485080.6	n.*65-57C>T		intron_variant	Intron 3 of 4	5		ENSP00000466643.1
SREBF1	ENST00000578469.1	n.*65-3C>T		splice_region_variant, intron_variant	Intron 2 of 2	3		ENSP00000465747.1

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

GnomAD2 exomes AF: 0.453 AC: 60745 AN: 134044 AF XY: 0.461

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 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

African (AFR) AF: 0.257 AC: 2155 AN: 8378

American (AMR) AF: 0.560 AC: 15073 AN: 26928

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 3595 AN: 10688

East Asian (EAS) AF: 0.846 AC: 7495 AN: 8860

South Asian (SAS) AF: 0.666 AC: 39599 AN: 59498

European-Finnish (FIN) AF: 0.324 AC: 4119 AN: 12732

Middle Eastern (MID) AF: 0.371 AC: 1027 AN: 2766

European-Non Finnish (NFE) AF: 0.306 AC: 48287 AN: 157940

Other (OTH) AF: 0.363 AC: 5124 AN: 14122

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

African (AFR) AF: 0.256 AC: 10638 AN: 41490

American (AMR) AF: 0.446 AC: 6811 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1108 AN: 3472

East Asian (EAS) AF: 0.845 AC: 4372 AN: 5172

South Asian (SAS) AF: 0.675 AC: 3247 AN: 4812

European-Finnish (FIN) AF: 0.337 AC: 3563 AN: 10560

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20593 AN: 67972

Other (OTH) AF: 0.328 AC: 692 AN: 2110

Alfa AF: 0.327 Hom.: 28469

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
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11868035; hg19: chr17-17715101;