rs3134031

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153704.6(TMEM67):ā€‹c.1810A>Gā€‹(p.Ile604Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.614 in 1,610,204 control chromosomes in the GnomAD database, including 305,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.65 ( 32347 hom., cov: 33)
Exomes š‘“: 0.61 ( 273246 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.282
Variant links:
Genes affected
TMEM67 (HGNC:28396): (transmembrane protein 67) The protein encoded by this gene localizes to the primary cilium and to the plasma membrane. The gene functions in centriole migration to the apical membrane and formation of the primary cilium. Multiple transcript variants encoding different isoforms have been found for this gene. Defects in this gene are a cause of Meckel syndrome type 3 (MKS3) and Joubert syndrome type 6 (JBTS6). [provided by RefSeq, Nov 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=8.642796E-7).
BP6
Variant 8-93795937-A-G is Benign according to our data. Variant chr8-93795937-A-G is described in ClinVar as [Benign]. Clinvar id is 126301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93795937-A-G is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMEM67NM_153704.6 linkuse as main transcriptc.1810A>G p.Ile604Val missense_variant 18/28 ENST00000453321.8 NP_714915.3 Q5HYA8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMEM67ENST00000453321.8 linkuse as main transcriptc.1810A>G p.Ile604Val missense_variant 18/281 NM_153704.6 ENSP00000389998.3 Q5HYA8

Frequencies

GnomAD3 genomes
AF:
0.648
AC:
98564
AN:
152010
Hom.:
32297
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.727
Gnomad AMI
AF:
0.684
Gnomad AMR
AF:
0.680
Gnomad ASJ
AF:
0.660
Gnomad EAS
AF:
0.731
Gnomad SAS
AF:
0.643
Gnomad FIN
AF:
0.572
Gnomad MID
AF:
0.611
Gnomad NFE
AF:
0.599
Gnomad OTH
AF:
0.630
GnomAD3 exomes
AF:
0.640
AC:
160774
AN:
251218
Hom.:
52192
AF XY:
0.634
AC XY:
86047
AN XY:
135796
show subpopulations
Gnomad AFR exome
AF:
0.734
Gnomad AMR exome
AF:
0.740
Gnomad ASJ exome
AF:
0.660
Gnomad EAS exome
AF:
0.734
Gnomad SAS exome
AF:
0.623
Gnomad FIN exome
AF:
0.573
Gnomad NFE exome
AF:
0.597
Gnomad OTH exome
AF:
0.628
GnomAD4 exome
AF:
0.610
AC:
889740
AN:
1458076
Hom.:
273246
Cov.:
36
AF XY:
0.610
AC XY:
442352
AN XY:
725528
show subpopulations
Gnomad4 AFR exome
AF:
0.738
Gnomad4 AMR exome
AF:
0.730
Gnomad4 ASJ exome
AF:
0.663
Gnomad4 EAS exome
AF:
0.722
Gnomad4 SAS exome
AF:
0.625
Gnomad4 FIN exome
AF:
0.579
Gnomad4 NFE exome
AF:
0.596
Gnomad4 OTH exome
AF:
0.618
GnomAD4 genome
AF:
0.649
AC:
98676
AN:
152128
Hom.:
32347
Cov.:
33
AF XY:
0.649
AC XY:
48260
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.727
Gnomad4 AMR
AF:
0.680
Gnomad4 ASJ
AF:
0.660
Gnomad4 EAS
AF:
0.730
Gnomad4 SAS
AF:
0.643
Gnomad4 FIN
AF:
0.572
Gnomad4 NFE
AF:
0.599
Gnomad4 OTH
AF:
0.635
Alfa
AF:
0.612
Hom.:
69815
Bravo
AF:
0.660
TwinsUK
AF:
0.601
AC:
2229
ALSPAC
AF:
0.608
AC:
2344
ESP6500AA
AF:
0.729
AC:
3211
ESP6500EA
AF:
0.595
AC:
5117
ExAC
AF:
0.637
AC:
77325
Asia WGS
AF:
0.670
AC:
2334
AN:
3476
EpiCase
AF:
0.599
EpiControl
AF:
0.608

ClinVar

Significance: Benign
Submissions summary: Benign:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJul 26, 2017- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Meckel syndrome, type 3 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Nephronophthisis 11 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Joubert syndrome 6 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
COACH syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
6.9
DANN
Benign
0.71
DEOGEN2
Benign
0.36
T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.0083
N
LIST_S2
Benign
0.058
T;T
MetaRNN
Benign
8.6e-7
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-1.5
N;.
PrimateAI
Benign
0.26
T
PROVEAN
Benign
0.39
N;N
REVEL
Benign
0.17
Sift
Benign
0.48
T;T
Sift4G
Benign
0.39
T;T
Polyphen
0.0
B;.
Vest4
0.020
MPC
0.097
ClinPred
0.00053
T
GERP RS
0.32
Varity_R
0.026
gMVP
0.19

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

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

Other links and lift over

dbSNP: rs3134031; hg19: chr8-94808165; COSMIC: COSV60038748; COSMIC: COSV60038748; API