19-648132-G-T

Variant names:

• chr19-648132-G-T
• rs566974599
• NM_194460.3:c.932C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_194460.3(RNF126):​c.932C>A​(p.Ser311*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RNF126 NM_194460.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.81
• Publications: 0 publications found

Genes affected

RNF126 (HGNC:21151): (ring finger protein 126) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF126	NM_194460.3	c.932C>A	p.Ser311*	stop_gained	Exon 9 of 9	ENST00000292363.10	NP_919442.1
RNF126	NM_001366018.1	c.851C>A	p.Ser284*	stop_gained	Exon 9 of 9		NP_001352947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10	c.932C>A	p.Ser311*	stop_gained	Exon 9 of 9	1	NM_194460.3	ENSP00000292363.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431160 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 707386

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32982

American (AMR) AF: 0.0000233 AC: 1 AN: 42972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24628

East Asian (EAS) AF: 0.00 AC: 0 AN: 39090

South Asian (SAS) AF: 0.00 AC: 0 AN: 82588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092838

Other (OTH) AF: 0.00 AC: 0 AN: 58910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	42
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.8
Vest4		0.0080
GERP RS		3.9
Mutation Taster		=71/129	disease causing

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: rs566974599; hg19: chr19-648132;