chr17-17813574-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004176.5(SREBF1):c.3097C>T(p.Arg1033Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000276 in 1,595,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1033L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

SREBF1
NM_004176.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.10

Publications

0 publications found

Variant links:

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 links:

MIR6777 (HGNC:50173): (microRNA 6777) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6777 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 41 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SREBF1	NM_004176.5	MANE Select	c.3097C>T	p.Arg1033Trp	missense	Exon 17 of 19	NP_004167.3
SREBF1	NM_001005291.3		c.3187C>T	p.Arg1063Trp	missense	Exon 18 of 20	NP_001005291.1	P36956-4
SREBF1	NM_001388385.1		c.3184C>T	p.Arg1062Trp	missense	Exon 16 of 18	NP_001375314.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SREBF1	ENST00000261646.11	TSL:1 MANE Select	c.3097C>T	p.Arg1033Trp	missense	Exon 17 of 19	ENSP00000261646.5	P36956-1
SREBF1	ENST00000355815.8	TSL:1	c.3187C>T	p.Arg1063Trp	missense	Exon 18 of 20	ENSP00000348069.4	P36956-4
SREBF1	ENST00000892469.1		c.3181C>T	p.Arg1061Trp	missense	Exon 18 of 20	ENSP00000562529.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000330

AC:

AN:

212326

AF XY:

0.0000426

show subpopulations

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:

0.0000320

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000284

AC:

AN:

1443390

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

717236

show subpopulations

African (AFR)

AF:

0.0000604

AC:

AN:

33130

American (AMR)

AF:

0.00

AC:

AN:

43458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25866

East Asian (EAS)

AF:

0.00

AC:

AN:

38992

South Asian (SAS)

AF:

0.000154

AC:

AN:

84300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45722

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000208

AC:

AN:

1106420

Other (OTH)

AF:

0.0000335

AC:

AN:

59748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000836

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000333

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.072

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.5

PhyloP100

3.1

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.25

Sift

Uncertain

0.0070

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.72

MutPred

0.43

Loss of disorder (P = 0.0054)

MVP

0.34

MPC

0.99

ClinPred

0.92

GERP RS

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.40

Mutation Taster

=64/36

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over