7-122702369-T-C

Position:

• chr7-122702369-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198085.2(RNF148):​c.382A>G​(p.Ile128Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RNF148 NM_198085.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

Genes affected

RNF148 (HGNC:22411): (ring finger protein 148) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in ubiquitin-dependent protein catabolic process. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus; endoplasmic reticulum; and late endosome. [provided by Alliance of Genome Resources, Apr 2022]

CADPS2 (HGNC:16018): (calcium dependent secretion activator 2) This gene encodes a member of the calcium-dependent activator of secretion (CAPS) protein family, which are calcium binding proteins that regulate the exocytosis of synaptic and dense-core vesicles in neurons and neuroendocrine cells. Mutations in this gene may contribute to autism susceptibility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12668037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF148	NM_198085.2	c.382A>G	p.Ile128Val	missense_variant	1/1	ENST00000434824.2	NP_932351.1
CADPS2	NM_017954.11	c.453+34586A>G		intron_variant		ENST00000449022.7	NP_060424.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF148	ENST00000434824.2	c.382A>G	p.Ile128Val	missense_variant	1/1	6	NM_198085.2	ENSP00000388207.1
CADPS2	ENST00000449022.7	c.453+34586A>G		intron_variant		5	NM_017954.11	ENSP00000398481.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461582 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727084

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 22, 2023

The c.382A>G (p.I128V) alteration is located in exon 1 (coding exon 1) of the RNF148 gene. This alteration results from a A to G substitution at nucleotide position 382, causing the isoleucine (I) at amino acid position 128 to be replaced by a valine (V). 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	0.22
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.071
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.19	B
Vest4		0.36
MutPred		0.57		Loss of sheet (P = 0.0457);
MVP		0.048
MPC		0.019
ClinPred		0.35	T
GERP RS		5.0
Varity_R		0.044
gMVP		0.060

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-122342423;