X-106773038-A-T

Position:

• chrX-106773038-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_194463.2(RNF128):​c.610A>T​(p.Asn204Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00795 in 1,209,373 control chromosomes in the GnomAD database, including 38 homozygotes. There are 3,024 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (3 hom., 142 hem., cov: 22)
  • Exomes 𝑓: 0.0082 (35 hom. 2882 hem.)
• Consequence: RNF128 NM_194463.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.98

Genes affected

RNF128 (HGNC:21153): (ring finger protein 128) The protein encoded by this gene is a type I transmembrane protein that localizes to the endocytic pathway. This protein contains a RING zinc-finger motif and has been shown to possess E3 ubiquitin ligase activity. Expression of this gene in retrovirally transduced T cell hybridoma significantly inhibits activation-induced IL2 and IL4 cytokine production. Induced expression of this gene was observed in anergic CD4(+) T cells, which suggested a role in the induction of anergic phenotype. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00972724).
• BP6: Variant X-106773038-A-T is Benign according to our data. Variant chrX-106773038-A-T is described in ClinVar as [Benign]. Clinvar id is 787195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-106773038-A-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF128	NM_194463.2	c.610A>T	p.Asn204Tyr	missense_variant	2/7	ENST00000255499.3	NP_919445.1
RNF128	NM_024539.3	c.532A>T	p.Asn178Tyr	missense_variant	2/7		NP_078815.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF128	ENST00000255499.3	c.610A>T	p.Asn204Tyr	missense_variant	2/7	1	NM_194463.2	ENSP00000255499	P2
RNF128	ENST00000324342.7	c.532A>T	p.Asn178Tyr	missense_variant	2/7	1		ENSP00000316127	A1
RNF128	ENST00000418562.5	c.451A>T	p.Asn151Tyr	missense_variant	3/6	5		ENSP00000412610

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 589 AN: 111219 Hom.: 3 Cov.: 22 AF XY: 0.00425 AC XY: 142 AN XY: 33407

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.00115

Gnomad ASJ AF: 0.0310

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000378

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.00853

Gnomad OTH AF: 0.00401

GnomAD3 exomes AF: 0.00577 AC: 1058 AN: 183393 Hom.: 8 AF XY: 0.00545 AC XY: 370 AN XY: 67855

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.0322

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.00886

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00822 AC: 9027 AN: 1098105 Hom.: 35 Cov.: 30 AF XY: 0.00793 AC XY: 2882 AN XY: 363503

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000483

Gnomad4 ASJ exome AF: 0.0344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00345

Gnomad4 NFE exome AF: 0.00933

Gnomad4 OTH exome AF: 0.00712

GnomAD4 genome AF: 0.00529 AC: 589 AN: 111268 Hom.: 3 Cov.: 22 AF XY: 0.00424 AC XY: 142 AN XY: 33466

Gnomad4 AFR AF: 0.000652

Gnomad4 AMR AF: 0.00115

Gnomad4 ASJ AF: 0.0310

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000379

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.00853

Gnomad4 OTH AF: 0.00396

Alfa AF: 0.00932 Hom.: 213

Bravo AF: 0.00474

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0111 AC: 32

ESP6500AA AF: 0.00130 AC: 5

ESP6500EA AF: 0.00892 AC: 60

ExAC AF: 0.00568 AC: 689

EpiCase AF: 0.00938

EpiControl AF: 0.00848

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;T;T
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.2	.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.75, 0.77
MVP		0.67
MPC		1.2
ClinPred		0.024	T
GERP RS		5.8
Varity_R		0.87
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs56121637; hg19: chrX-106016268;