17-17812813-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004176.5(SREBF1):​c.3253G>A​(p.Glu1085Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000268 in 1,491,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SREBF1 NM_004176.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

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>A	p.Glu1085Lys	missense	Exon 19 of 19	NP_004167.3
	SREBF1	NM_001005291.3		c.3343G>A	p.Glu1115Lys	missense	Exon 20 of 20	NP_001005291.1	P36956-4
	SREBF1	NM_001388385.1		c.3340G>A	p.Glu1114Lys	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>A	p.Glu1085Lys	missense	Exon 19 of 19	ENSP00000261646.5	P36956-1
	SREBF1	ENST00000355815.8	TSL:1	c.3343G>A	p.Glu1115Lys	missense	Exon 20 of 20	ENSP00000348069.4	P36956-4
	SREBF1	ENST00000892469.1		c.3337G>A	p.Glu1113Lys	missense	Exon 20 of 20	ENSP00000562529.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000224 AC: 3 AN: 1339404 Hom.: 0 Cov.: 31 AF XY: 0.00000456 AC XY: 3 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: 0.00000284 AC: 3 AN: 1058116

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.97	D
Vest4		0.80
MutPred		0.34		Gain of ubiquitination at E1085 (P = 0.0069)
MVP		0.38
MPC		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.75
gMVP		0.76
Mutation Taster		=34/66	disease causing

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;