7-122698916-C-T

Variant names:

• chr7-122698916-C-T
• rs71574716
• NM_139175.2:c.3G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PVS1_Supporting BS1 BS2

The NM_139175.2(RNF133):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,569,222 control chromosomes in the GnomAD database, including 1,660 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (185 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1475 hom.)
• Consequence: RNF133 NM_139175.2 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.79

Genes affected

RNF133 (HGNC:21154): (ring finger protein 133) 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. This gene has no intron. [provided by RefSeq, Jul 2008]

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 Benign. Variant got -7 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 19 codons. Genomic position: 122698864. Lost 0.049 part of the original CDS.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0359 (5464/152242) while in subpopulation NFE AF= 0.0491 (3341/68010). AF 95% confidence interval is 0.0477. There are 185 homozygotes in gnomad4. There are 2725 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 185 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF133	NM_139175.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 1	ENST00000340112.3	NP_631914.1
CADPS2	NM_017954.11	c.454-35347G>A		intron_variant	Intron 2 of 29	ENST00000449022.7	NP_060424.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF133	ENST00000340112.3	c.3G>A	p.Met1?	start_lost	Exon 1 of 1	6	NM_139175.2	ENSP00000344489.2
CADPS2	ENST00000449022.7	c.454-35347G>A		intron_variant	Intron 2 of 29	5	NM_017954.11	ENSP00000398481.2
CADPS2	ENST00000412584.6	c.454-35347G>A		intron_variant	Intron 2 of 27	1		ENSP00000400401.2
CADPS2	ENST00000313070.11	c.136-35347G>A		intron_variant	Intron 2 of 29	5		ENSP00000325581.8

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5468 AN: 152124 Hom.: 185 Cov.: 33

Gnomad AFR AF: 0.00707

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0324

Gnomad ASJ AF: 0.0328

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0413 AC: 8611 AN: 208270 Hom.: 250 AF XY: 0.0411 AC XY: 4589 AN XY: 111536

Gnomad AFR exome AF: 0.00639

Gnomad AMR exome AF: 0.0468

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.0203

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0446

Gnomad OTH exome AF: 0.0455

GnomAD4 exome AF: 0.0393 AC: 55720 AN: 1416980 Hom.: 1475 Cov.: 30 AF XY: 0.0390 AC XY: 27347 AN XY: 701212

Gnomad4 AFR exome AF: 0.00471

Gnomad4 AMR exome AF: 0.0427

Gnomad4 ASJ exome AF: 0.0344

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.0195

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.0405

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0359 AC: 5464 AN: 152242 Hom.: 185 Cov.: 33 AF XY: 0.0366 AC XY: 2725 AN XY: 74444

Gnomad4 AFR AF: 0.00705

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.0328

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0168

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0491

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0392 Hom.: 194

Bravo AF: 0.0279

TwinsUK AF: 0.0364 AC: 135

ALSPAC AF: 0.0374 AC: 144

ESP6500AA AF: 0.00659 AC: 29

ESP6500EA AF: 0.0425 AC: 363

ExAC AF: 0.0388 AC: 4696

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.046	B
Vest4		0.33
MutPred		0.97		Loss of disorder (P = 0.0682);
ClinPred		0.067	T
GERP RS		4.8
Varity_R		0.89
gMVP		0.32

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: rs71574716; hg19: chr7-122338970; COSMIC: COSV99069445; COSMIC: COSV99069445;