5-159161405-T-C

Variant names:

• chr5-159161405-T-C
• rs1237176495
• NM_001199383.2:c.1487A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001199383.2(RNF145):​c.1487A>G​(p.Tyr496Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000219 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: RNF145 NM_001199383.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

RNF145 (HGNC:20853): (ring finger protein 145) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in protein ubiquitination. Predicted to be located in endoplasmic reticulum membrane. Predicted to be integral component of membrane. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF145	NM_001199383.2	c.1487A>G	p.Tyr496Cys	missense_variant	Exon 10 of 11	ENST00000424310.7	NP_001186312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF145	ENST00000424310.7	c.1487A>G	p.Tyr496Cys	missense_variant	Exon 10 of 11	1	NM_001199383.2	ENSP00000409064.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251480 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1577A>G (p.Y526C) alteration is located in exon 10 (coding exon 10) of the RNF145 gene. This alteration results from a A to G substitution at nucleotide position 1577, causing the tyrosine (Y) at amino acid position 526 to be replaced by a cysteine (C). 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	0.28
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T;T;T;.;.;.
Eigen	Benign	-0.020
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;.;.;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.34	.;N;N;N;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.4	D;D;D;.;.;D;D
REVEL	Uncertain	0.55
Sift	Benign	0.066	T;T;T;.;.;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T
Polyphen		0.057	B;B;B;B;.;.;.
Vest4		0.90
MutPred		0.53		.;Loss of MoRF binding (P = 0.0903);Loss of MoRF binding (P = 0.0903);Loss of MoRF binding (P = 0.0903);.;.;.;
MVP		0.88
MPC		2.0
ClinPred		0.43	T
GERP RS		6.1
Varity_R		0.36
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1237176495; hg19: chr5-158588413;