chr17-17821475-G-A

Variant names:

• chr17-17821475-G-A
• rs11656665
• NM_004176.5:c.92-954C>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.92-954C>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 151,848 control chromosomes in the GnomAD database, including 18,140 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 (18140 hom., cov: 31)
• Consequence: SREBF1 NM_004176.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 14 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF1	NM_004176.5	MANE Select	c.92-954C>T		intron	N/A	NP_004167.3
	SREBF1	NM_001005291.3		c.182-954C>T		intron	N/A	NP_001005291.1
	SREBF1	NM_001388385.1		c.92-954C>T		intron	N/A	NP_001375314.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF1	ENST00000261646.11	TSL:1 MANE Select	c.92-954C>T		intron	N/A	ENSP00000261646.5
	SREBF1	ENST00000355815.8	TSL:1	c.182-954C>T		intron	N/A	ENSP00000348069.4
	SREBF1	ENST00000395757.6	TSL:2	c.92-954C>T		intron	N/A	ENSP00000379106.2

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68047 AN: 151730 Hom.: 18134 Cov.: 31

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.540

Gnomad EAS AF: 0.0794

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.623

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: 68084 AN: 151848 Hom.: 18140 Cov.: 31 AF XY: 0.440 AC XY: 32629 AN XY: 74222

African (AFR) AF: 0.202 AC: 8381 AN: 41410

American (AMR) AF: 0.411 AC: 6275 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 1870 AN: 3464

East Asian (EAS) AF: 0.0792 AC: 410 AN: 5174

South Asian (SAS) AF: 0.262 AC: 1261 AN: 4808

European-Finnish (FIN) AF: 0.560 AC: 5894 AN: 10530

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42334 AN: 67902

Other (OTH) AF: 0.476 AC: 1002 AN: 2104

Alfa AF: 0.526 Hom.: 8650

Bravo AF: 0.429

Asia WGS AF: 0.237 AC: 827 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.70
DANN	Benign	0.37
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs11656665; hg19: chr17-17724789;