rs537247534

Positions:

• chr22-20425454-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000622235.5(SCARF2):​c.2522C>T​(p.Thr841Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,418,186 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: SCARF2 ENST00000622235.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 8.35

Genes affected

SCARF2 (HGNC:19869): (scavenger receptor class F member 2) The protein encoded by this gene is similar to SCARF1/SREC-I, a scavenger receptor protein that mediates the binding and degradation of acetylated low density lipoprotein (Ac-LDL). This protein has only little activity of internalizing modified low density lipoproteins (LDL), but it can interact with SCARF1 through its extracellular domain. The association of this protein with SCARF1 is suppressed by the presence of scavenger ligands. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007663578).
• BP6: Variant 22-20425454-G-A is Benign according to our data. Variant chr22-20425454-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436646.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00116 (1463/1266008) while in subpopulation MID AF= 0.0152 (64/4214). AF 95% confidence interval is 0.0122. There are 6 homozygotes in gnomad4_exome. There are 754 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCARF2	NM_182895.5	c.2522C>T	p.Thr841Ile	missense_variant	11/11	ENST00000622235.5	NP_878315.2
SCARF2	NM_153334.7	c.2537C>T	p.Thr846Ile	missense_variant	11/11		NP_699165.3
SCARF2	XM_047441585.1	c.2636C>T	p.Thr879Ile	missense_variant	11/11		XP_047297541.1
SCARF2	XM_017029065.3	c.*751C>T		3_prime_UTR_variant	11/11		XP_016884554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARF2	ENST00000622235.5	c.2522C>T	p.Thr841Ile	missense_variant	11/11	1	NM_182895.5	ENSP00000477564	P1
SCARF2	ENST00000623402.1	c.2537C>T	p.Thr846Ile	missense_variant	11/11	1		ENSP00000485276

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152070 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0155

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00111 AC: 123 AN: 111090 Hom.: 3 AF XY: 0.00123 AC XY: 80 AN XY: 65078

Gnomad AFR exome AF: 0.000322

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.000269

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00525

GnomAD4 exome AF: 0.00116 AC: 1463 AN: 1266008 Hom.: 6 Cov.: 31 AF XY: 0.00121 AC XY: 754 AN XY: 620950

Gnomad4 AFR exome AF: 0.000760

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000838

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 81 AN XY: 74414

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00147

ExAC AF: 0.00104 AC: 118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	SCARF2: BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 08, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.62	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.81	N;N
PrimateAI	Pathogenic	0.96	D
Sift4G	Uncertain	0.044	D;T
Vest4		0.42
MVP		0.23
ClinPred		0.051	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.51

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: rs537247534; hg19: chr22-20779744;