rs9902941

Variant names:

• chr17-17830446-C-T
• rs9902941
• NM_004176.5:c.91+6281G>A

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+6281G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 152,198 control chromosomes in the GnomAD database, including 23,878 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 0.55 (23878 hom., cov: 34)
• Consequence: SREBF1 NM_004176.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.46
• Publications: 29 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.627 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+6281G>A		intron	N/A	NP_004167.3
	SREBF1	NM_001005291.3		c.91+6281G>A		intron	N/A	NP_001005291.1	P36956-4
	SREBF1	NM_001388385.1		c.91+6281G>A		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+6281G>A		intron	N/A	ENSP00000261646.5	P36956-1
	SREBF1	ENST00000355815.8	TSL:1	c.91+6281G>A		intron	N/A	ENSP00000348069.4	P36956-4
	SREBF1	ENST00000892469.1		c.91+6281G>A		intron	N/A	ENSP00000562529.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83316 AN: 152080 Hom.: 23862 Cov.: 34

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.0827

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.557

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

GnomAD4 genome AF: 0.548 AC: 83384 AN: 152198 Hom.: 23878 Cov.: 34 AF XY: 0.536 AC XY: 39919 AN XY: 74428

African (AFR) AF: 0.522 AC: 21668 AN: 41516

American (AMR) AF: 0.466 AC: 7130 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2002 AN: 3472

East Asian (EAS) AF: 0.0827 AC: 428 AN: 5176

South Asian (SAS) AF: 0.280 AC: 1353 AN: 4826

European-Finnish (FIN) AF: 0.565 AC: 5986 AN: 10592

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42973 AN: 68004

Other (OTH) AF: 0.556 AC: 1175 AN: 2112

Alfa AF: 0.600 Hom.: 49734

Bravo AF: 0.541

Asia WGS AF: 0.260 AC: 905 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.14
DANN	Benign	0.39
PhyloP100		-1.5
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: rs9902941; hg19: chr17-17733760;