rs9899634

chr17-17824629-T-Achr17-17824629-T-C

Variant summary

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

The NM_004176.5(SREBF1):c.92-4108A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 151,972 control chromosomes in the GnomAD database, including 21,402 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 0.51 (21402 hom., cov: 32)
• Consequence: SREBF1 NM_004176.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.583

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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SREBF1	NM_004176.5	c.92-4108A>T		intron_variant		ENST00000261646.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SREBF1	ENST00000261646.11	c.92-4108A>T		intron_variant		1	NM_004176.5	P4
SREBF1	ENST00000355815.8	c.92-1022A>T		intron_variant		1		A2
SREBF1	ENST00000395757.6	c.92-4108A>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77855 AN: 151854 Hom.: 21380 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.0813

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.530

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

GnomAD4 genome AF: 0.513 AC: 77928 AN: 151972 Hom.: 21402 Cov.: 32 AF XY: 0.502 AC XY: 37316 AN XY: 74290

Gnomad4 AFR AF: 0.402

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.0813

Gnomad4 SAS AF: 0.280

Gnomad4 FIN AF: 0.565

Gnomad4 NFE AF: 0.632

Gnomad4 OTH AF: 0.529

Alfa AF: 0.437 Hom.: 1274

Bravo AF: 0.501

Asia WGS AF: 0.255 AC: 887 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	5.5
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs9899634; hg19: chr17-17727943;