19-648174-G-T

Variant names:

• chr19-648174-G-T
• rs1310579319
• NM_194460.3:c.890C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_194460.3(RNF126):​c.890C>A​(p.Ser297Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,454,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. S297F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RNF126 NM_194460.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.40
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2799324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF126	NM_194460.3	c.890C>A	p.Ser297Tyr	missense_variant	Exon 9 of 9	ENST00000292363.10	NP_919442.1
RNF126	NM_001366018.1	c.809C>A	p.Ser270Tyr	missense_variant	Exon 9 of 9		NP_001352947.1
RNF126	XM_047439069.1	c.*314C>A		downstream_gene_variant			XP_047295025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10	c.890C>A	p.Ser297Tyr	missense_variant	Exon 9 of 9	1	NM_194460.3	ENSP00000292363.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454146 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722336

⚠️ 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: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 85448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107380

Other (OTH) AF: 0.00 AC: 0 AN: 59984

⚠️ 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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		6.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.17
Sift	Benign	0.20	T;.
Sift4G	Uncertain	0.014	D;.
Vest4		0.42
MutPred		0.37		Loss of relative solvent accessibility (P = 0.0186);.;
MVP		0.26
MPC		0.26
ClinPred		0.82	D
GERP RS		3.6
Varity_R		0.18
Mutation Taster		=33/67	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: rs1310579319; hg19: chr19-648174;