Variant 19-12949145-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005053.4(RAD23A):c.665C>T(p.Pro222Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

RAD23A
NM_005053.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.59

Variant links:

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]

RAD23A links:

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ACMG classification

Classification made for transcript

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=0.13373244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RAD23A	NM_005053.4 linkuse as main transcript	c.665C>T	p.Pro222Leu	missense_variant	6/9	ENST00000586534.6
RAD23A	NM_001270362.2 linkuse as main transcript	c.665C>T	p.Pro222Leu	missense_variant	6/9
RAD23A	NM_001270363.2 linkuse as main transcript	c.665C>T	p.Pro222Leu	missense_variant	6/8
RAD23A	NR_072976.2 linkuse as main transcript	n.696C>T		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD23A	ENST00000586534.6 linkuse as main transcript	c.665C>T	p.Pro222Leu	missense_variant	6/9	1	NM_005053.4	A1	P54725-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250126

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135298

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000448

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:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.665C>T (p.P222L) alteration is located in exon 6 (coding exon 6) of the RAD23A gene. This alteration results from a C to T substitution at nucleotide position 665, causing the proline (P) at amino acid position 222 to be replaced by a leucine (L). 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

0.075

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.42

.;T;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;T;T;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.2

D;.;.;.

REVEL

Benign

0.046

Sift

Benign

0.10

T;.;.;.

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.20

.;B;.;.

Vest4

0.47

MutPred

0.19

Gain of stability (P = 0.047);Gain of stability (P = 0.047);Gain of stability (P = 0.047);.;

MVP

0.66

MPC

0.42

ClinPred

0.27

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.093

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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