rs147603937

Variant names:

• chr17-17813395-G-A
• rs147603937
• NM_004176.5:c.3187C>T

Variant summary

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

The NM_004176.5(SREBF1):​c.3187C>T​(p.Arg1063Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,600,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: SREBF1 NM_004176.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.908
• Publications: 1 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]

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]

ACMG classification

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

• BS2: High AC in GnomAd4 at 13 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.3187C>T	p.Arg1063Trp	missense	Exon 18 of 19	NP_004167.3
	SREBF1	NM_001005291.3		c.3277C>T	p.Arg1093Trp	missense	Exon 19 of 20	NP_001005291.1	P36956-4
	SREBF1	NM_001388385.1		c.3274C>T	p.Arg1092Trp	missense	Exon 17 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.3187C>T	p.Arg1063Trp	missense	Exon 18 of 19	ENSP00000261646.5	P36956-1
	SREBF1	ENST00000355815.8	TSL:1	c.3277C>T	p.Arg1093Trp	missense	Exon 19 of 20	ENSP00000348069.4	P36956-4
	SREBF1	ENST00000892469.1		c.3271C>T	p.Arg1091Trp	missense	Exon 19 of 20	ENSP00000562529.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000807 AC: 18 AN: 222942 AF XY: 0.000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000203 AC: 294 AN: 1448764 Hom.: 0 Cov.: 33 AF XY: 0.000178 AC XY: 128 AN XY: 719710

African (AFR) AF: 0.0000301 AC: 1 AN: 33240

American (AMR) AF: 0.0000228 AC: 1 AN: 43802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.000178 AC: 15 AN: 84390

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4996

European-Non Finnish (NFE) AF: 0.000237 AC: 262 AN: 1107310

Other (OTH) AF: 0.000234 AC: 14 AN: 59770

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000831 AC: 10

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	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.91
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.40
MPC		1.0
ClinPred		0.91	D
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.71
gMVP		0.55
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs147603937; hg19: chr17-17716709;