19-651620-G-C

Variant names:

• chr19-651620-G-C
• rs1003755092
• NM_194460.3:c.434C>G

Variant summary

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

The NM_194460.3(RNF126):​c.434C>G​(p.Thr145Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000775 in 1,289,544 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T145M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: RNF126 NM_194460.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.35
• 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.434C>G	p.Thr145Arg	missense_variant	Exon 4 of 9	ENST00000292363.10	NP_919442.1
RNF126	XM_047439069.1	c.434C>G	p.Thr145Arg	missense_variant	Exon 4 of 8		XP_047295025.1
RNF126	NM_001366018.1	c.362+72C>G		intron_variant	Intron 4 of 8		NP_001352947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10	c.434C>G	p.Thr145Arg	missense_variant	Exon 4 of 9	1	NM_194460.3	ENSP00000292363.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.75e-7 AC: 1 AN: 1289544 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 630406

African (AFR) AF: 0.00 AC: 0 AN: 26042

American (AMR) AF: 0.00 AC: 0 AN: 20240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18418

East Asian (EAS) AF: 0.00 AC: 0 AN: 32730

South Asian (SAS) AF: 0.00 AC: 0 AN: 64236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4006

European-Non Finnish (NFE) AF: 9.68e-7 AC: 1 AN: 1032906

Other (OTH) AF: 0.00 AC: 0 AN: 52412

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.092	T
Vest4		0.93
MutPred		0.36		Gain of MoRF binding (P = 0.0235);
MVP		0.42
MPC		0.79
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.63
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs1003755092; hg19: chr19-651620;