rs1889018

Variant names:

• chr17-17831426-G-A
• rs1889018
• NM_004176.5:c.91+5301C>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.91+5301C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 151,762 control chromosomes in the GnomAD database, including 18,382 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 0.45 (18382 hom., cov: 30)
• Consequence: SREBF1 NM_004176.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58
• Publications: 24 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, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004176.5. 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
	SREBF1	NM_004176.5	MANE Select	c.91+5301C>T		intron	N/A	NP_004167.3
	SREBF1	NM_001005291.3		c.91+5301C>T		intron	N/A	NP_001005291.1	P36956-4
	SREBF1	NM_001388385.1		c.91+5301C>T		intron	N/A	NP_001375314.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF1	ENST00000261646.11	TSL:1 MANE Select	c.91+5301C>T		intron	N/A	ENSP00000261646.5	P36956-1
	SREBF1	ENST00000355815.8	TSL:1	c.91+5301C>T		intron	N/A	ENSP00000348069.4	P36956-4
	SREBF1	ENST00000892469.1		c.91+5301C>T		intron	N/A	ENSP00000562529.1

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68022 AN: 151644 Hom.: 18379 Cov.: 30

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.0674

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.473

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.448 AC: 68047 AN: 151762 Hom.: 18382 Cov.: 30 AF XY: 0.440 AC XY: 32587 AN XY: 74120

African (AFR) AF: 0.189 AC: 7846 AN: 41410

American (AMR) AF: 0.421 AC: 6413 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1908 AN: 3464

East Asian (EAS) AF: 0.0672 AC: 346 AN: 5152

South Asian (SAS) AF: 0.267 AC: 1280 AN: 4800

European-Finnish (FIN) AF: 0.563 AC: 5929 AN: 10532

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42674 AN: 67852

Other (OTH) AF: 0.473 AC: 998 AN: 2108

Alfa AF: 0.566 Hom.: 35945

Bravo AF: 0.429

Asia WGS AF: 0.228 AC: 795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.091
DANN	Benign	0.53
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1889018; hg19: chr17-17734740;