rs17848351

chr22-41898747-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004599.4(SREBF2):c.2704G>C(p.Val902Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,614,176 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: SREBF2 NM_004599.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.25

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009077609).
• BP6: Variant 22-41898747-G-C is Benign according to our data. Variant chr22-41898747-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3044042.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SREBF2	NM_004599.4	c.2704G>C	p.Val902Leu	missense_variant	15/19	ENST00000361204.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SREBF2	ENST00000361204.9	c.2704G>C	p.Val902Leu	missense_variant	15/19	1	NM_004599.4	P3

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000633 AC: 159 AN: 251304 Hom.: 0 AF XY: 0.000604 AC XY: 82 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00636

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000386 AC: 564 AN: 1461854 Hom.: 2 Cov.: 31 AF XY: 0.000395 AC XY: 287 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0103

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.0000629

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00965

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000340 Hom.: 0

Bravo AF: 0.000484

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SREBF2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Benign	0.096	T
Sift4G	Uncertain	0.013	D
Polyphen		0.96	D
Vest4		0.44
MutPred		0.33		Loss of methylation at K907 (P = 0.0793);
MVP		0.21
MPC		0.17
ClinPred		0.072	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs17848351; hg19: chr22-42294751;