17-17812813-C-G

Variant names:

• chr17-17812813-C-G
• rs2033043563
• NM_004176.5:c.3253G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004176.5(SREBF1):​c.3253G>C​(p.Glu1085Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,339,404 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1085K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: SREBF1 NM_004176.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3253G>C	p.Glu1085Gln	missense	Exon 19 of 19	NP_004167.3
	SREBF1	NM_001005291.3		c.3343G>C	p.Glu1115Gln	missense	Exon 20 of 20	NP_001005291.1	P36956-4
	SREBF1	NM_001388385.1		c.3340G>C	p.Glu1114Gln	missense	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.3253G>C	p.Glu1085Gln	missense	Exon 19 of 19	ENSP00000261646.5	P36956-1
	SREBF1	ENST00000355815.8	TSL:1	c.3343G>C	p.Glu1115Gln	missense	Exon 20 of 20	ENSP00000348069.4	P36956-4
	SREBF1	ENST00000892469.1		c.3337G>C	p.Glu1113Gln	missense	Exon 20 of 20	ENSP00000562529.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1339404 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 657198

African (AFR) AF: 0.00 AC: 0 AN: 29180

American (AMR) AF: 0.00 AC: 0 AN: 27998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23174

East Asian (EAS) AF: 0.00 AC: 0 AN: 34260

South Asian (SAS) AF: 0.00 AC: 0 AN: 73430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4012

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058116

Other (OTH) AF: 0.00 AC: 0 AN: 55766

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.29
Sift	Benign	0.071	T
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.74
MutPred		0.19		Gain of glycosylation at P1081 (P = 0.1768)
MVP		0.35
MPC		0.97
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.52
gMVP		0.62

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: rs2033043563; hg19: chr17-17716127;