NM_004176.5:c.1069-48G>A

Variant names:

• chr17-17818422-C-T
• rs12601420
• NM_004176.5:c.1069-48G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004176.5(SREBF1):​c.1069-48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 1,476,608 control chromosomes in the GnomAD database, including 2,035 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.030 (295 hom., cov: 31)
  • Exomes 𝑓: 0.027 (1740 hom.)
• Consequence: SREBF1 NM_004176.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437
• 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]

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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF1	NM_004176.5	MANE Select	c.1069-48G>A		intron	N/A	NP_004167.3
	SREBF1	NM_001005291.3		c.1159-48G>A		intron	N/A	NP_001005291.1
	SREBF1	NM_001388385.1		c.1069-48G>A		intron	N/A	NP_001375314.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF1	ENST00000261646.11	TSL:1 MANE Select	c.1069-48G>A		intron	N/A	ENSP00000261646.5
	SREBF1	ENST00000355815.8	TSL:1	c.1159-48G>A		intron	N/A	ENSP00000348069.4
	SREBF1	ENST00000469356.3	TSL:3	n.321G>A		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4563 AN: 151688 Hom.: 292 Cov.: 31

Gnomad AFR AF: 0.00723

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0859

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.0150

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0293

GnomAD2 exomes AF: 0.0513 AC: 12244 AN: 238444 AF XY: 0.0454

Gnomad AFR exome AF: 0.00686

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.290

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0366

GnomAD4 exome AF: 0.0270 AC: 35807 AN: 1324802 Hom.: 1740 Cov.: 19 AF XY: 0.0257 AC XY: 17083 AN XY: 665598

African (AFR) AF: 0.00496 AC: 152 AN: 30660

American (AMR) AF: 0.116 AC: 5060 AN: 43588

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 496 AN: 25280

East Asian (EAS) AF: 0.236 AC: 9164 AN: 38840

South Asian (SAS) AF: 0.0119 AC: 988 AN: 82970

European-Finnish (FIN) AF: 0.0301 AC: 1551 AN: 51564

Middle Eastern (MID) AF: 0.00823 AC: 35 AN: 4252

European-Non Finnish (NFE) AF: 0.0165 AC: 16375 AN: 991872

Other (OTH) AF: 0.0356 AC: 1986 AN: 55776

GnomAD4 genome AF: 0.0301 AC: 4571 AN: 151806 Hom.: 295 Cov.: 31 AF XY: 0.0327 AC XY: 2422 AN XY: 74166

African (AFR) AF: 0.00720 AC: 298 AN: 41364

American (AMR) AF: 0.0868 AC: 1324 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.273 AC: 1405 AN: 5142

South Asian (SAS) AF: 0.0150 AC: 72 AN: 4792

European-Finnish (FIN) AF: 0.0303 AC: 320 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1034 AN: 67928

Other (OTH) AF: 0.0281 AC: 59 AN: 2102

Alfa AF: 0.0218 Hom.: 48

Bravo AF: 0.0372

Asia WGS AF: 0.118 AC: 410 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.9
DANN	Benign	0.42
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12601420; hg19: chr17-17721736; COSMIC: COSV55419013; COSMIC: COSV55419013;