19-12948746-A-C

Variant names:

• chr19-12948746-A-C
• rs565619875
• NM_005053.4:c.533A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005053.4(RAD23A):​c.533A>C​(p.Glu178Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RAD23A NM_005053.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.00

Genes affected

RAD23A (HGNC:9812): (RAD23 homolog A, nucleotide excision repair protein) The protein encoded by this gene is one of two human homologs of Saccharomyces cerevisiae Rad23, a protein involved in nucleotide excision repair. Proteins in this family have a modular domain structure consisting of an ubiquitin-like domain (UbL), ubiquitin-associated domain 1 (UbA1), XPC-binding domain and UbA2. The protein encoded by this gene plays an important role in nucleotide excision repair and also in delivery of polyubiquitinated proteins to the proteasome. Alternative splicing results in multiple transcript variants encoding multiple isoforms. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25390607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD23A	NM_005053.4	c.533A>C	p.Glu178Ala	missense_variant	Exon 5 of 9	ENST00000586534.6	NP_005044.1
RAD23A	NM_001270362.2	c.533A>C	p.Glu178Ala	missense_variant	Exon 5 of 9		NP_001257291.1
RAD23A	NM_001270363.2	c.533A>C	p.Glu178Ala	missense_variant	Exon 5 of 8		NP_001257292.1
RAD23A	NR_072976.2	n.564A>C		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD23A	ENST00000586534.6	c.533A>C	p.Glu178Ala	missense_variant	Exon 5 of 9	1	NM_005053.4	ENSP00000467024.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250730 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135560

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

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: 0.00000274 AC: 4 AN: 1461454 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727076

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74418

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.533A>C (p.E178A) alteration is located in exon 5 (coding exon 5) of the RAD23A gene. This alteration results from a A to C substitution at nucleotide position 533, causing the glutamic acid (E) at amino acid position 178 to be replaced by an alanine (A). 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	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.9	D;.;.
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D;.;.
Sift4G	Benign	0.14	T;T;T
Polyphen		0.43	.;B;.
Vest4		0.31
MutPred		0.56		Gain of MoRF binding (P = 0.0211);Gain of MoRF binding (P = 0.0211);Gain of MoRF binding (P = 0.0211);
MVP		0.79
MPC		1.1
ClinPred		0.92	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.76

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: rs565619875; hg19: chr19-13059560;