chr22-41871601-C-A

Variant names:

• chr22-41871601-C-A
• rs133290
• NM_004599.4:c.867+566C>A

Variant summary

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

The NM_004599.4(SREBF2):​c.867+566C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 151,998 control chromosomes in the GnomAD database, including 29,567 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 0.61 (29567 hom., cov: 32)
• Consequence: SREBF2 NM_004599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.220
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SREBF2	NM_004599.4	c.867+566C>A		intron_variant	Intron 4 of 18	ENST00000361204.9	NP_004590.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SREBF2	ENST00000361204.9	c.867+566C>A		intron_variant	Intron 4 of 18	1	NM_004599.4	ENSP00000354476.4
SREBF2	ENST00000424354.5	n.867+566C>A		intron_variant	Intron 4 of 21	1		ENSP00000395728.1
SREBF2	ENST00000710853.1	c.777+566C>A		intron_variant	Intron 4 of 18			ENSP00000518526.1

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91940 AN: 151880 Hom.: 29517 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.574

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.606 AC: 92042 AN: 151998 Hom.: 29567 Cov.: 32 AF XY: 0.602 AC XY: 44747 AN XY: 74310

African (AFR) AF: 0.810 AC: 33578 AN: 41456

American (AMR) AF: 0.669 AC: 10227 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2129 AN: 3470

East Asian (EAS) AF: 0.715 AC: 3704 AN: 5182

South Asian (SAS) AF: 0.551 AC: 2659 AN: 4824

European-Finnish (FIN) AF: 0.428 AC: 4518 AN: 10552

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.492 AC: 33421 AN: 67922

Other (OTH) AF: 0.568 AC: 1198 AN: 2108

Alfa AF: 0.538 Hom.: 12645

Bravo AF: 0.637

Asia WGS AF: 0.598 AC: 2081 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.8
DANN	Benign	0.37
PhyloP100		0.22
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: rs133290; hg19: chr22-42267605;