19-648945-G-T

Variant names:

• chr19-648945-G-T
• rs1176499565
• NM_194460.3:c.607C>A

Variant summary

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

The NM_194460.3(RNF126):​c.607C>A​(p.Pro203Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000782 in 1,279,290 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. P203S) 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: 9.89
• 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.607C>A	p.Pro203Thr	missense_variant	Exon 7 of 9	ENST00000292363.10	NP_919442.1
RNF126	NM_001366018.1	c.526C>A	p.Pro176Thr	missense_variant	Exon 7 of 9		NP_001352947.1
RNF126	XM_047439069.1	c.684C>A	p.Pro228Pro	synonymous_variant	Exon 7 of 8		XP_047295025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10	c.607C>A	p.Pro203Thr	missense_variant	Exon 7 of 9	1	NM_194460.3	ENSP00000292363.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.82e-7 AC: 1 AN: 1279290 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 621654

⚠️ 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: 27000

American (AMR) AF: 0.00 AC: 0 AN: 21496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17960

East Asian (EAS) AF: 0.00 AC: 0 AN: 33594

South Asian (SAS) AF: 0.00 AC: 0 AN: 52670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3910

European-Non Finnish (NFE) AF: 9.76e-7 AC: 1 AN: 1024126

Other (OTH) AF: 0.00 AC: 0 AN: 51990

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	M;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.043	D;.
Vest4		0.66
MutPred		0.37		Loss of catalytic residue at P202 (P = 0.0194);.;
MVP		0.31
MPC		0.84
ClinPred		1.0	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
Mutation Taster		=35/65	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: rs1176499565; hg19: chr19-648945;