chr7-7639074-T-C

Position:

• chr7-7639074-T-C

Variant summary

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

The NM_002947.5(RPA3):​c.170A>G​(p.Glu57Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPA3 NM_002947.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

Genes affected

RPA3 (HGNC:10291): (replication protein A3) Enables damaged DNA binding activity and single-stranded DNA binding activity. Involved in DNA repair and DNA replication. Part of DNA replication factor A complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA3	NM_002947.5	c.170A>G	p.Glu57Gly	missense_variant	6/8	ENST00000223129.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA3	ENST00000223129.8	c.170A>G	p.Glu57Gly	missense_variant	6/8	1	NM_002947.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249722 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

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: 0.00000137 AC: 2 AN: 1458132 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000451

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 Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2024

The c.170A>G (p.E57G) alteration is located in exon 6 (coding exon 2) of the RPA3 gene. This alteration results from a A to G substitution at nucleotide position 170, causing the glutamic acid (E) at amino acid position 57 to be replaced by a glycine (G). 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	0.22
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	.;.;T;T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.34	B;.;B;.
Vest4		0.53
MutPred		0.52		Loss of stability (P = 0.0631);.;Loss of stability (P = 0.0631);.;
MVP		0.54
MPC		0.24
ClinPred		0.97	D
GERP RS		4.6
Varity_R		0.43
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs769104678; hg19: chr7-7678705;