Genetic Variant SCARA5:p.His495Tyr (chr8-27871939-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_173833.6(SCARA5):c.1483C>T(p.His495Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCARA5
NM_173833.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.389

Variant links:

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]

SCARA5 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05950609).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARA5	NM_173833.6 link	c.1483C>T	p.His495Tyr	missense_variant	Exon 9 of 9	ENST00000354914.8	NP_776194.2	Q6ZMJ2-1
SCARA5	NM_001413201.1 link	c.1354C>T	p.His452Tyr	missense_variant	Exon 8 of 8		NP_001400130.1
SCARA5	NM_001413203.1 link	c.679C>T	p.His227Tyr	missense_variant	Exon 8 of 8		NP_001400132.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARA5	ENST00000354914.8 link	c.1483C>T	p.His495Tyr	missense_variant	Exon 9 of 9	2	NM_173833.6	ENSP00000346990.3		Q6ZMJ2-1
SCARA5	ENST00000380385.6 link	c.808C>T	p.His270Tyr	missense_variant	Exon 8 of 8	1		ENSP00000369746.2		Q6ZMJ2-4

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251390

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000205

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1483C>T (p.H495Y) alteration is located in exon 9 (coding exon 8) of the SCARA5 gene. This alteration results from a C to T substitution at nucleotide position 1483, causing the histidine (H) at amino acid position 495 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.5

DANN

Benign

0.97

DEOGEN2

Benign

0.044

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.3

L;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.70

N;N

REVEL

Benign

0.20

Sift

Benign

0.062

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;B

Vest4

0.12

MVP

0.55

MPC

0.29

ClinPred

0.028

GERP RS

3.0

Varity_R

0.19

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over