chr17-17812839-T-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004176.5(SREBF1):c.3227A>G(p.Glu1076Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000876 in 1,472,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000088 ( 0 hom. )
Consequence
SREBF1
NM_004176.5 missense
NM_004176.5 missense
Scores
1
4
13
Clinical Significance
Conservation
PhyloP100: 2.00
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2043648).
BS2
?
High AC in GnomAd at 13 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SREBF1 | NM_004176.5 | c.3227A>G | p.Glu1076Gly | missense_variant | 19/19 | ENST00000261646.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SREBF1 | ENST00000261646.11 | c.3227A>G | p.Glu1076Gly | missense_variant | 19/19 | 1 | NM_004176.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152098Hom.: 0 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000254 AC: 2AN: 78670Hom.: 0 AF XY: 0.0000457 AC XY: 2AN XY: 43804
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GnomAD4 exome AF: 0.0000879 AC: 116AN: 1320238Hom.: 0 Cov.: 31 AF XY: 0.0000773 AC XY: 50AN XY: 647060
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GnomAD4 genome ? AF: 0.0000855 AC: 13AN: 152098Hom.: 0 Cov.: 33 AF XY: 0.0000808 AC XY: 6AN XY: 74298
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2023 | The c.3227A>G (p.E1076G) alteration is located in exon 19 (coding exon 19) of the SREBF1 gene. This alteration results from a A to G substitution at nucleotide position 3227, causing the glutamic acid (E) at amino acid position 1076 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;D;D
Sift4G
Uncertain
D;D;D
Polyphen
0.81, 0.39
.;P;B
Vest4
MutPred
0.27
.;.;Gain of MoRF binding (P = 0.0506);
MVP
MPC
0.43
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at