1-32937182-G-A

Variant names:

• chr1-32937182-G-A
• rs75240537
• NM_001300826.2:c.1820C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001300826.2(RNF19B):​c.1820C>T​(p.Thr607Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,614,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000079 (1 hom.)
• Consequence: RNF19B NM_001300826.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04
• Publications: 0 publications found

Genes affected

RNF19B (HGNC:26886): (ring finger protein 19B) This gene encodes a multi-pass membrane protein containing two RING-type and one IBR-type zinc finger motifs. The encoded protin is an E3 ubiquitin-protein ligase that plays a role in the cytotoxic effects of natural killer (NK) cells. Alternative splicing results in multiple transcript variants. There are pseudogenes for this gene on chromosomes X and Y in a possible pseudoautosomal region. [provided by RefSeq, Jul 2014]

ENSG00000287691 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039360195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF19B	NM_001300826.2	c.1820C>T	p.Thr607Met	missense_variant	Exon 9 of 9	ENST00000235150.5	NP_001287755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF19B	ENST00000235150.5	c.1820C>T	p.Thr607Met	missense_variant	Exon 9 of 9	1	NM_001300826.2	ENSP00000235150.4

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000677 AC: 17 AN: 251260 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000794 AC: 116 AN: 1461876 Hom.: 1 Cov.: 33 AF XY: 0.0000784 AC XY: 57 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000845 AC: 94 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152210 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74424

African (AFR) AF: 0.0000241 AC: 1 AN: 41518

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000443 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1823C>T (p.T608M) alteration is located in exon 9 (coding exon 9) of the RNF19B gene. This alteration results from a C to T substitution at nucleotide position 1823, causing the threonine (T) at amino acid position 608 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		2.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.070
Sift	Uncertain	0.024	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.017	B;.
Vest4		0.13
MVP		0.082
MPC		0.68
ClinPred		0.17	T
GERP RS		3.0
Varity_R		0.037
gMVP		0.28
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs75240537; hg19: chr1-33402783;