4-153710412-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_173662.4(RNF175):c.944T>C(p.Ile315Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I315M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RNF175 NM_173662.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

Genes affected

RNF175 (HGNC:27735): (ring finger protein 175) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in ubiquitin-dependent ERAD pathway. Predicted to be integral component of membrane. Predicted to be active in Golgi membrane and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

TLR2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27952778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF175	NM_173662.4	c.944T>C	p.Ile315Thr	missense_variant	9/9	ENST00000347063.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF175	ENST00000347063.9	c.944T>C	p.Ile315Thr	missense_variant	9/9	1	NM_173662.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424028 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 704546

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.944T>C (p.I315T) alteration is located in exon 9 (coding exon 9) of the RNF175 gene. This alteration results from a T to C substitution at nucleotide position 944, causing the isoleucine (I) at amino acid position 315 to be replaced by a threonine (T). 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	0.23
BayesDel_addAF	Benign	0.0010	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.16
Sift	Benign	0.091	T
Sift4G	Benign	0.10	T
Polyphen		0.64	P
Vest4		0.43
MutPred		0.41		Loss of sheet (P = 7e-04);
MVP		0.43
MPC		0.29
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.34
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs1250695710; hg19: chr4-154631564;