Genetic Variant NM_194460.3:c.893C>T (chr19-648171-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_194460.3(RNF126):c.893C>T(p.Ser298Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,846 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: 0.0000021 ( 0 hom. )

Consequence

RNF126
NM_194460.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.81

Variant links:

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]

RNF126 links:

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ACMG classification

Classification was made for transcript

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 link	c.893C>T	p.Ser298Phe	missense_variant	Exon 9 of 9	ENST00000292363.10	NP_919442.1	Q9BV68A0A024R206A8K0Q1
RNF126	NM_001366018.1 link	c.812C>T	p.Ser271Phe	missense_variant	Exon 9 of 9		NP_001352947.1
RNF126	XM_047439069.1 link	c.*317C>T		downstream_gene_variant			XP_047295025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10 link	c.893C>T	p.Ser298Phe	missense_variant	Exon 9 of 9	1	NM_194460.3	ENSP00000292363.3		Q9BV68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1453846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722122

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33340

American (AMR)

AF:

0.00

AC:

AN:

44226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25924

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

85546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107018

Other (OTH)

AF:

0.00

AC:

AN:

59952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.893C>T (p.S298F) alteration is located in exon 9 (coding exon 9) of the RNF126 gene. This alteration results from a C to T substitution at nucleotide position 893, causing the serine (S) at amino acid position 298 to be replaced by a phenylalanine (F). 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

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

PhyloP100

9.8

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

D;.

REVEL

Benign

0.24

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0090

D;.

Vest4

0.42

MutPred

0.33

Loss of phosphorylation at S298 (P = 3e-04);.;

MVP

0.24

MPC

0.22

ClinPred

0.98

GERP RS

3.6

Varity_R

0.42

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_194460.3:c.893C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over