NM_005506.4:c.*117G>A

Variant names:

• chr4-76161596-C-T
• rs3733255
• NM_005506.4:c.*117G>A

Variant summary

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

The NM_005506.4(SCARB2):​c.*117G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00804 in 1,058,144 control chromosomes in the GnomAD database, including 222 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 0.024 (110 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (112 hom.)
• Consequence: SCARB2 NM_005506.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.90
• Publications: 5 publications found

Genes affected

SCARB2 (HGNC:1665): (scavenger receptor class B member 2) The protein encoded by this gene is a type III glycoprotein that is located primarily in limiting membranes of lysosomes and endosomes. Earlier studies in mice and rat suggested that this protein may participate in membrane transportation and the reorganization of endosomal/lysosomal compartment. The protein deficiency in mice was reported to impair cell membrane transport processes and cause pelvic junction obstruction, deafness, and peripheral neuropathy. Further studies in human showed that this protein is a ubiquitously expressed protein and that it is involved in the pathogenesis of HFMD (hand, foot, and mouth disease) caused by enterovirus-71 and possibly by coxsackievirus A16. Mutations in this gene caused an autosomal recessive progressive myoclonic epilepsy-4 (EPM4), also known as action myoclonus-renal failure syndrome (AMRF). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

SCARB2 Gene-Disease associations (from GenCC):

• action myoclonus-renal failure syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• progressive myoclonus epilepsy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Unverricht-Lundborg syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286074 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.*117G>A		3_prime_UTR_variant	Exon 12 of 12	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.*117G>A		3_prime_UTR_variant	Exon 9 of 9		NP_001191184.1
SCARB2	XM_047416429.1	c.*117G>A		3_prime_UTR_variant	Exon 12 of 12		XP_047272385.1
SCARB2	XM_047416430.1	c.*117G>A		3_prime_UTR_variant	Exon 12 of 12		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.*117G>A		3_prime_UTR_variant	Exon 12 of 12	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3603 AN: 152124 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.0503

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0187

GnomAD4 exome AF: 0.00540 AC: 4890 AN: 905902 Hom.: 112 Cov.: 12 AF XY: 0.00504 AC XY: 2384 AN XY: 472914

African (AFR) AF: 0.0740 AC: 1680 AN: 22706

American (AMR) AF: 0.00427 AC: 185 AN: 43314

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 26 AN: 22572

East Asian (EAS) AF: 0.0481 AC: 1781 AN: 37056

South Asian (SAS) AF: 0.00293 AC: 219 AN: 74698

European-Finnish (FIN) AF: 0.000783 AC: 40 AN: 51100

Middle Eastern (MID) AF: 0.00918 AC: 43 AN: 4682

European-Non Finnish (NFE) AF: 0.000900 AC: 547 AN: 607700

Other (OTH) AF: 0.00877 AC: 369 AN: 42074

GnomAD4 genome AF: 0.0237 AC: 3615 AN: 152242 Hom.: 110 Cov.: 32 AF XY: 0.0234 AC XY: 1741 AN XY: 74436

African (AFR) AF: 0.0733 AC: 3043 AN: 41538

American (AMR) AF: 0.00974 AC: 149 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.0504 AC: 261 AN: 5182

South Asian (SAS) AF: 0.00581 AC: 28 AN: 4820

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68022

Other (OTH) AF: 0.0190 AC: 40 AN: 2108

Alfa AF: 0.00945 Hom.: 62

Bravo AF: 0.0271

Asia WGS AF: 0.0220 AC: 75 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

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.014
DANN	Benign	0.56
PhyloP100		-4.9
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: rs3733255; hg19: chr4-77082749; COSMIC: COSV53670106; COSMIC: COSV53670106;