Genetic Variant NM_002945.5:c.12A>T (chr17-1830105-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002945.5(RPA1):c.12A>T(p.Gln4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q4Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RPA1
NM_002945.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

Publications

24 publications found

Variant links:

Genes affected

RPA1 (HGNC:10289): (replication protein A1) This gene encodes the largest subunit of the heterotrimeric Replication Protein A (RPA) complex, which binds to single-stranded DNA (ssDNA), forming a nucleoprotein complex that plays an important role in DNA metabolism, being involved in DNA replication, repair, recombination, telomere maintenance, and co-ordinating the cellular response to DNA damage through activation of the ataxia telangiectasia and Rad3-related protein (ATR) kinase. The nucleoprotein complex protects the single-stranded DNA from nucleases, prevents formation of secondary structures that would interfere with repair, and co-ordinates the recruitment and departure of different genome maintenance factors. This subunit contains four oligonucleotide/oligosaccharide-binding (OB) domains, though the majority of ssDNA binding occurs in two of these domains. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which ssDNA binding domains are utilized. The different binding modes differ in the length of DNA bound and in the proteins with which it interacts, thereby playing a role in regulating different genomic maintenance pathways. [provided by RefSeq, Sep 2017]

RPA1 links:

SMYD4 (HGNC:21067): (SET and MYND domain containing 4) Predicted to enable metal ion binding activity and methyltransferase activity. Involved in heart development. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SMYD4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041728973).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002945.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPA1	NM_002945.5	MANE Select	c.12A>T	p.Gln4His	missense	Exon 1 of 17	NP_002936.1	P27694
RPA1	NM_001355121.2		c.12A>T	p.Gln4His	missense	Exon 1 of 16	NP_001342050.1
RPA1	NM_001355120.2		c.-36A>T		5_prime_UTR	Exon 1 of 17	NP_001342049.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPA1	ENST00000254719.10	TSL:1 MANE Select	c.12A>T	p.Gln4His	missense	Exon 1 of 17	ENSP00000254719.4	P27694
RPA1	ENST00000852058.1		c.12A>T	p.Gln4His	missense	Exon 1 of 18	ENSP00000522117.1
RPA1	ENST00000852055.1		c.12A>T	p.Gln4His	missense	Exon 1 of 18	ENSP00000522114.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1097470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

518458

African (AFR)

AF:

0.00

AC:

AN:

23098

American (AMR)

AF:

0.00

AC:

AN:

8568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14370

East Asian (EAS)

AF:

0.00

AC:

AN:

26672

South Asian (SAS)

AF:

0.00

AC:

AN:

19686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4402

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920712

Other (OTH)

AF:

0.00

AC:

AN:

43948

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

9303

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

9.3

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.074

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.53

M_CAP

Benign

0.017

MetaRNN

Benign

0.042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PhyloP100

-1.2

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.55

REVEL

Benign

0.057

Sift

Benign

0.40

Sift4G

Benign

0.17

Polyphen

0.0

Vest4

0.078

MutPred

0.55

Gain of disorder (P = 0.1804)

MVP

0.37

MPC

0.20

ClinPred

0.046

GERP RS

-9.9

PromoterAI

0.19

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.22

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over