7-122702077-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198085.2(RNF148):​c.674G>A​(p.Arg225Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000394 in 1,613,406 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00024 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

RNF148
NM_198085.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.681
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.024981141).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RNF148NM_198085.2 linkuse as main transcriptc.674G>A p.Arg225Gln missense_variant 1/1 ENST00000434824.2 NP_932351.1
CADPS2NM_017954.11 linkuse as main transcriptc.453+34878G>A intron_variant ENST00000449022.7 NP_060424.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RNF148ENST00000434824.2 linkuse as main transcriptc.674G>A p.Arg225Gln missense_variant 1/1 NM_198085.2 ENSP00000388207 P1
CADPS2ENST00000449022.7 linkuse as main transcriptc.453+34878G>A intron_variant 5 NM_017954.11 ENSP00000398481 Q86UW7-1

Frequencies

GnomAD3 genomes
AF:
0.000243
AC:
37
AN:
152090
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000229
AC:
57
AN:
248504
Hom.:
0
AF XY:
0.000267
AC XY:
36
AN XY:
134782
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.000291
Gnomad ASJ exome
AF:
0.0000996
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000355
Gnomad OTH exome
AF:
0.000498
GnomAD4 exome
AF:
0.000409
AC:
598
AN:
1461316
Hom.:
1
Cov.:
32
AF XY:
0.000392
AC XY:
285
AN XY:
726924
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000291
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000496
Gnomad4 OTH exome
AF:
0.000331
GnomAD4 genome
AF:
0.000243
AC:
37
AN:
152090
Hom.:
1
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.000956
Alfa
AF:
0.000408
Hom.:
0
Bravo
AF:
0.000295
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000363
AC:
3
ExAC
AF:
0.000199
AC:
24
EpiCase
AF:
0.000600
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 02, 2022The c.674G>A (p.R225Q) alteration is located in exon 1 (coding exon 1) of the RNF148 gene. This alteration results from a G to A substitution at nucleotide position 674, causing the arginine (R) at amino acid position 225 to be replaced by a glutamine (Q). 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
0.071
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
4.8
DANN
Benign
0.59
DEOGEN2
Benign
0.024
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.95
FATHMM_MKL
Benign
0.078
N
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.0066
T
MetaRNN
Benign
0.025
T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
-0.18
N
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
2.3
N
REVEL
Benign
0.083
Sift
Benign
1.0
T
Sift4G
Benign
0.68
T
Polyphen
0.0020
B
Vest4
0.092
MVP
0.067
MPC
0.0040
ClinPred
0.0099
T
GERP RS
1.5
Varity_R
0.026
gMVP
0.043

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs202200728; hg19: chr7-122342131; COSMIC: COSV57361707; COSMIC: COSV57361707; API