8-100258713-G-A

Position:

• chr8-100258713-G-A

Variant summary

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

The NM_183419.4(RNF19A):​c.2360C>T​(p.Ser787Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF19A NM_183419.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

Genes affected

RNF19A (HGNC:13432): (ring finger protein 19A, RBR E3 ubiquitin protein ligase) This gene encodes a member of the ring between ring fingers (RBR) protein family, and the encoded protein contains two RING-finger motifs and an in between RING fingers motif. This protein is an E3 ubiquitin ligase that is localized to Lewy bodies, and ubiquitylates synphilin-1, which is an interacting protein of alpha synuclein in neurons. The encoded protein may be involved in amyotrophic lateral sclerosis and Parkinson's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

SPAG1 (HGNC:11212): (sperm associated antigen 1) The correlation of anti-sperm antibodies with cases of unexplained infertility implicates a role for these antibodies in blocking fertilization. Improved diagnosis and treatment of immunologic infertility, as well as identification of proteins for targeted contraception, are dependent on the identification and characterization of relevant sperm antigens. The protein expressed by this gene is recognized by anti-sperm agglutinating antibodies from an infertile woman. Furthermore, immunization of female rats with the recombinant human protein reduced fertility. This protein localizes to the plasma membrane of germ cells in the testis and to the post-acrosomal plasma membrane of mature spermatozoa. Recombinant polypeptide binds GTP and exhibits GTPase activity. Thus, this protein may regulate GTP signal transduction pathways involved in spermatogenesis and fertilization. Two transcript variants of this gene encode the same protein. [provided by RefSeq, Jul 2008]

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=0.16399825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF19A	NM_183419.4	c.2360C>T	p.Ser787Leu	missense_variant	10/10	ENST00000341084.7	NP_904355.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF19A	ENST00000341084.7	c.2360C>T	p.Ser787Leu	missense_variant	10/10	5	NM_183419.4	ENSP00000342667.2
RNF19A	ENST00000519449.5	c.2360C>T	p.Ser787Leu	missense_variant	11/11	1		ENSP00000428968.1
SPAG1	ENST00000519409.1	n.214-329G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Oct 20, 2024

The c.2360C>T (p.S787L) alteration is located in exon 10 (coding exon 9) of the RNF19A gene. This alteration results from a C to T substitution at nucleotide position 2360, causing the serine (S) at amino acid position 787 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	0.072
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.078	T;T
Eigen	Benign	0.081
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.093	T;T
Polyphen		0.020	B;B
Vest4		0.15
MutPred		0.45		Loss of disorder (P = 0.0087);Loss of disorder (P = 0.0087);
MVP		0.70
MPC		0.15
ClinPred		0.57	D
GERP RS		5.1
Varity_R		0.15
gMVP		0.13

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: rs374144598; hg19: chr8-101270941; COSMIC: COSV61995226; COSMIC: COSV61995226;