Variant 14-23104829-G-A details in Genebe, Genetics Data Aggregator

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

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]

CIROP links:

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
CIROP	NM_001354640.2 link	c.92C>T	p.Ser31Phe	missense_variant	Exon 1 of 16	ENST00000637218.2	NP_001341569.1
CIROP	NM_001402427.1 link	c.92C>T	p.Ser31Phe	missense_variant	Exon 1 of 14		NP_001389356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CIROP	ENST00000637218.2 link	c.92C>T	p.Ser31Phe	missense_variant	Exon 1 of 16	5	NM_001354640.2	ENSP00000489869.1	A0A1B0GTW7-1
CIROP	ENST00000644000.1 link	c.92C>T	p.Ser31Phe	missense_variant	Exon 1 of 14			ENSP00000493582.1	A0A1B0GTW7-2
CIROP	ENST00000642668.1 link	c.17C>T	p.Ser6Phe	missense_variant	Exon 1 of 13			ENSP00000495729.1	A0A2R8Y752
CIROP	ENST00000644147.1 link	n.140C>T		non_coding_transcript_exon_variant	Exon 1 of 9

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

162

AN:

152102

Hom.:

Cov.:

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.:

AF XY:

0.00122

AC XY:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.000860

AC XY:

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.:

Bravo

AF:

0.00126

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00363

AC:

ExAC

AF:

0.000519

AC:

Asia WGS

AF:

0.000289

AC:

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 provided

literature only

OMIM

Mar 15, 2022

- -

CIROP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2023

This 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

DANN

Benign

0.82

FATHMM_MKL

Benign

0.66

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over