17-17812003-C-T

Position:

• chr17-17812003-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004176.5(SREBF1):​c.*619G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000665 in 285,816 control chromosomes in the GnomAD database, including 1 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: not found (cov: 33)
  • Exomes 𝑓: 0.000066 (1 hom.)
• Consequence: SREBF1 NM_004176.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SREBF1	NM_004176.5	c.*619G>A		3_prime_UTR_variant	19/19	ENST00000261646.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SREBF1	ENST00000261646.11	c.*619G>A		3_prime_UTR_variant	19/19	1	NM_004176.5	P4
SREBF1	ENST00000395757.6	c.3156G>A	p.Gly1052=	synonymous_variant	18/19	2
SREBF1	ENST00000485080.6	c.*34G>A		3_prime_UTR_variant, NMD_transcript_variant	3/5	5
SREBF1	ENST00000578469.1	c.*34G>A		3_prime_UTR_variant, NMD_transcript_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000748 AC: 9 AN: 120346 Hom.: 0 AF XY: 0.000106 AC XY: 7 AN XY: 66186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000410

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000199

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000665 AC: 19 AN: 285816 Hom.: 1 Cov.: 0 AF XY: 0.0000791 AC XY: 13 AN XY: 164320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000317

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000651

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.1
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2297508; hg19: chr17-17715317;