17-1830105-A-C

Variant names:

• chr17-1830105-A-C
• rs5030749
• NM_002945.5:c.12A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002945.5(RPA1):​c.12A>C​(p.Gln4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,474 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 9.1e-7 (0 hom.)
• Consequence: RPA1 NM_002945.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 0 publications found

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]

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]

ACMG classification

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=0.04174179).

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097474 Hom.: 0 Cov.: 50 AF XY: 0.00 AC XY: 0 AN XY: 518462

African (AFR) AF: 0.00 AC: 0 AN: 23098

American (AMR) AF: 0.00 AC: 0 AN: 8568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14370

East Asian (EAS) AF: 0.0000375 AC: 1 AN: 26672

South Asian (SAS) AF: 0.00 AC: 0 AN: 19686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4402

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920712

Other (OTH) AF: 0.00 AC: 0 AN: 43948

GnomAD4 genome Cov.: 31

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	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.6
DANN	Benign	0.80
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.058
Sift	Benign	0.40	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.078
MutPred		0.55		Gain of disorder (P = 0.1804)
MVP		0.37
MPC		0.20
ClinPred		0.055	T
GERP RS		-9.9
PromoterAI		-0.0012	Neutral
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

Other links and lift over

dbSNP: rs5030749; hg19: chr17-1733399;