8-27921699-C-T

Variant names:

• chr8-27921699-C-T
• rs765044292
• NM_173833.6:c.788G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173833.6(SCARA5):​c.788G>A​(p.Arg263His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 1,451,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R263P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000090 (1 hom.)
• Consequence: SCARA5 NM_173833.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42
• Publications: 0 publications found

Genes affected

SCARA5 (HGNC:28701): (scavenger receptor class A member 5) Predicted to enable ferritin receptor activity. Predicted to be involved in several processes, including cellular iron ion homeostasis; iron ion transmembrane transport; and protein homotrimerization. Predicted to act upstream of or within cellular response to heat. Predicted to be located in cell surface. Predicted to be integral component of plasma membrane. Predicted to be active in external side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173833.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCARA5	NM_173833.6	MANE Select	c.788G>A	p.Arg263His	missense	Exon 4 of 9	NP_776194.2
	SCARA5	NM_001413201.1		c.659G>A	p.Arg220His	missense	Exon 3 of 8	NP_001400130.1
	SCARA5	NM_001413202.1		c.788G>A	p.Arg263His	missense	Exon 4 of 7	NP_001400131.1	Q6ZMJ2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCARA5	ENST00000354914.8	TSL:2 MANE Select	c.788G>A	p.Arg263His	missense	Exon 4 of 9	ENSP00000346990.3	Q6ZMJ2-1
	SCARA5	ENST00000524352.5	TSL:1	c.788G>A	p.Arg263His	missense	Exon 4 of 7	ENSP00000428663.1	Q6ZMJ2-2
	SCARA5	ENST00000518030.1	TSL:1	c.659G>A	p.Arg220His	missense	Exon 2 of 5	ENSP00000430713.1	Q6ZMJ2-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000178 AC: 4 AN: 224244 AF XY: 0.0000328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000896 AC: 13 AN: 1451016 Hom.: 1 Cov.: 31 AF XY: 0.0000180 AC XY: 13 AN XY: 720840

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 43382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.00 AC: 0 AN: 39292

South Asian (SAS) AF: 0.000154 AC: 13 AN: 84196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107814

Other (OTH) AF: 0.00 AC: 0 AN: 59918

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.62
Sift	Benign	0.035	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.73		Loss of MoRF binding (P = 0.0221)
MVP		0.96
MPC		1.0
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.14
gMVP		0.63
Mutation Taster		=72/28	polymorphism

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: rs765044292; hg19: chr8-27779216; COSMIC: COSV57277440;