17-17812003-C-T

Variant names:

• chr17-17812003-C-T
• rs2297508
• NM_004176.5:c.*619G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 61 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 -8 ACMG points.

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

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.*619G>A		3_prime_UTR	Exon 19 of 19	NP_004167.3
	SREBF1	NM_001005291.3		c.*619G>A		3_prime_UTR	Exon 20 of 20	NP_001005291.1	P36956-4
	SREBF1	NM_001388385.1		c.*619G>A		3_prime_UTR	Exon 18 of 18	NP_001375314.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF1	ENST00000261646.11	TSL:1 MANE Select	c.*619G>A		3_prime_UTR	Exon 19 of 19	ENSP00000261646.5	P36956-1
	SREBF1	ENST00000395757.6	TSL:2	c.3156G>A	p.Gly1052Gly	synonymous	Exon 18 of 19	ENSP00000379106.2	P36956-2
	SREBF1	ENST00000892469.1		c.*619G>A		3_prime_UTR	Exon 20 of 20	ENSP00000562529.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000748 AC: 9 AN: 120346 AF XY: 0.000106

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 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

African (AFR) AF: 0.00 AC: 0 AN: 6956

American (AMR) AF: 0.00 AC: 0 AN: 21688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10124

East Asian (EAS) AF: 0.00 AC: 0 AN: 7986

South Asian (SAS) AF: 0.000317 AC: 18 AN: 56848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2728

European-Non Finnish (NFE) AF: 0.00000651 AC: 1 AN: 153520

Other (OTH) AF: 0.00 AC: 0 AN: 13426

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 3164

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.1
DANN	Benign	0.87
PhyloP100		-0.024
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

Other links and lift over

dbSNP: rs2297508; hg19: chr17-17715317;