14-23104829-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001354640.2(CIROP):​c.92C>T​(p.Ser31Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 702,970 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

CIROP
NM_001354640.2 missense

Scores

6

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1B:1

Conservation

PhyloP100: 2.27
Variant links:
Genes affected
CIROP (HGNC:53647): (ciliated left-right organizer metallopeptidase) Predicted to enable peptidase activity. Predicted to be involved in cell adhesion and proteolysis. Predicted to be integral component of membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009967804).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00106 (161/152220) while in subpopulation NFE AF= 0.00197 (134/68016). AF 95% confidence interval is 0.0017. There are 1 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CIROPNM_001354640.2 linkc.92C>T p.Ser31Phe missense_variant Exon 1 of 16 ENST00000637218.2 NP_001341569.1
CIROPNM_001402427.1 linkc.92C>T p.Ser31Phe missense_variant Exon 1 of 14 NP_001389356.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CIROPENST00000637218.2 linkc.92C>T p.Ser31Phe missense_variant Exon 1 of 16 5 NM_001354640.2 ENSP00000489869.1 A0A1B0GTW7-1
CIROPENST00000644000.1 linkc.92C>T p.Ser31Phe missense_variant Exon 1 of 14 ENSP00000493582.1 A0A1B0GTW7-2
CIROPENST00000642668.1 linkc.17C>T p.Ser6Phe missense_variant Exon 1 of 13 ENSP00000495729.1 A0A2R8Y752
CIROPENST00000644147.1 linkn.140C>T non_coding_transcript_exon_variant Exon 1 of 9

Frequencies

GnomAD3 genomes
AF:
0.00107
AC:
162
AN:
152102
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00197
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.00120
AC:
162
AN:
134452
Hom.:
0
AF XY:
0.00122
AC XY:
89
AN XY:
73128
show subpopulations
Gnomad AFR exome
AF:
0.000617
Gnomad AMR exome
AF:
0.000572
Gnomad ASJ exome
AF:
0.000121
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000891
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00210
Gnomad OTH exome
AF:
0.00290
GnomAD4 exome
AF:
0.00135
AC:
746
AN:
550750
Hom.:
2
Cov.:
0
AF XY:
0.00132
AC XY:
394
AN XY:
298154
show subpopulations
Gnomad4 AFR exome
AF:
0.000696
Gnomad4 AMR exome
AF:
0.000518
Gnomad4 ASJ exome
AF:
0.000100
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00104
Gnomad4 FIN exome
AF:
0.0000297
Gnomad4 NFE exome
AF:
0.00189
Gnomad4 OTH exome
AF:
0.00147
GnomAD4 genome
AF:
0.00106
AC:
161
AN:
152220
Hom.:
1
Cov.:
32
AF XY:
0.000860
AC XY:
64
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00197
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.00150
Hom.:
0
Bravo
AF:
0.00126
TwinsUK
AF:
0.00216
AC:
8
ALSPAC
AF:
0.00363
AC:
14
ExAC
AF:
0.000519
AC:
18
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Heterotaxy, visceral, 12, autosomal Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 15, 2022- -
CIROP-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 28, 2023This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_noAF
Benign
-0.30
CADD
Benign
23
DANN
Benign
0.82
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.56
T;T;T
MetaRNN
Benign
0.010
T;T;T
GERP RS
5.5
Varity_R
0.28
gMVP
0.25

Splicing

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: rs553352307; hg19: chr14-23574038; API