NM_004599.4:c.868-174C>T

Variant names:

• chr22-41873624-C-T
• rs133291
• NM_004599.4:c.868-174C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004599.4(SREBF2):​c.868-174C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 655,314 control chromosomes in the GnomAD database, including 18,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3995 hom., cov: 32)
  • Exomes 𝑓: 0.23 (14448 hom.)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.59
• Publications: 27 publications found

Genes affected

SREBF2 (HGNC:11290): (sterol regulatory element binding transcription factor 2) This gene encodes a member of the a ubiquitously expressed transcription factor that controls cholesterol homeostasis by regulating transcription of sterol-regulated genes. The encoded protein contains a basic helix-loop-helix-leucine zipper (bHLH-Zip) domain and binds the sterol regulatory element 1 motif. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

SREBF2 Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-41873624-C-T is Benign according to our data. Variant chr22-41873624-C-T is described in ClinVar as Benign. ClinVar VariationId is 1287095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004599.4. 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
	SREBF2	NM_004599.4	MANE Select	c.868-174C>T		intron	N/A	NP_004590.2
	SREBF2	NR_103834.2		n.1034-174C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SREBF2	ENST00000361204.9	TSL:1 MANE Select	c.868-174C>T		intron	N/A	ENSP00000354476.4
	SREBF2	ENST00000424354.5	TSL:1	n.868-174C>T		intron	N/A	ENSP00000395728.1
	SREBF2	ENST00000710853.1		c.778-174C>T		intron	N/A	ENSP00000518526.1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33292 AN: 151842 Hom.: 3998 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.208

GnomAD4 exome AF: 0.231 AC: 116063 AN: 503354 Hom.: 14448 AF XY: 0.230 AC XY: 61367 AN XY: 266756

African (AFR) AF: 0.184 AC: 2583 AN: 14040

American (AMR) AF: 0.109 AC: 2837 AN: 26010

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 3855 AN: 16166

East Asian (EAS) AF: 0.397 AC: 12390 AN: 31218

South Asian (SAS) AF: 0.190 AC: 9961 AN: 52564

European-Finnish (FIN) AF: 0.217 AC: 7250 AN: 33402

Middle Eastern (MID) AF: 0.192 AC: 416 AN: 2164

European-Non Finnish (NFE) AF: 0.235 AC: 70311 AN: 299772

Other (OTH) AF: 0.231 AC: 6460 AN: 28018

GnomAD4 genome AF: 0.219 AC: 33284 AN: 151960 Hom.: 3995 Cov.: 32 AF XY: 0.218 AC XY: 16176 AN XY: 74276

African (AFR) AF: 0.182 AC: 7537 AN: 41436

American (AMR) AF: 0.151 AC: 2308 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 837 AN: 3472

East Asian (EAS) AF: 0.487 AC: 2516 AN: 5170

South Asian (SAS) AF: 0.187 AC: 900 AN: 4818

European-Finnish (FIN) AF: 0.233 AC: 2452 AN: 10546

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16062 AN: 67954

Other (OTH) AF: 0.207 AC: 434 AN: 2100

Alfa AF: 0.217 Hom.: 2531

Bravo AF: 0.212

Asia WGS AF: 0.275 AC: 957 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.022
DANN	Benign	0.48
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs133291; hg19: chr22-42269628;