rs3097427

Positions:

chr8-93782392-C-T

Variant summary

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

The NM_153704.6(TMEM67):c.1066-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,603,638 control chromosomes in the GnomAD database, including 294,521 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 32861 hom., cov: 31)

Exomes 𝑓: 0.60 ( 261660 hom. )

Consequence

TMEM67
NM_153704.6 splice_region, intron

Scores

Splicing: ADA: 0.0004581

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.0630

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]

TMEM67 links:

TMEM67 (HGNC:):

TMEM67 links:

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 (BayesDel_noAF=-0.79).

BP6

Variant 8-93782392-C-T is Benign according to our data. Variant chr8-93782392-C-T is described in ClinVar as [Benign]. Clinvar id is 96528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-93782392-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM67	NM_153704.6 linkuse as main transcript	c.1066-3C>T		splice_region_variant, intron_variant		ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 linkuse as main transcript	c.1066-3C>T		splice_region_variant, intron_variant		1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.651

AC:

98851

AN:

151840

Hom.:

32804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.764

Gnomad AMI

AF:

0.704

Gnomad AMR

AF:

0.668

Gnomad ASJ

AF:

0.627

Gnomad EAS

AF:

0.821

Gnomad SAS

AF:

0.632

Gnomad FIN

AF:

0.564

Gnomad MID

AF:

0.608

Gnomad NFE

AF:

0.582

Gnomad OTH

AF:

0.627

GnomAD3 exomes

AF:

0.636

AC:

159161

AN:

250398

Hom.:

51711

AF XY:

0.627

AC XY:

84865

AN XY:

135254

show subpopulations

Gnomad AFR exome

AF:

0.771

Gnomad AMR exome

AF:

0.725

Gnomad ASJ exome

AF:

0.628

Gnomad EAS exome

AF:

0.836

Gnomad SAS exome

AF:

0.609

Gnomad FIN exome

AF:

0.571

Gnomad NFE exome

AF:

0.578

Gnomad OTH exome

AF:

0.609

GnomAD4 exome

AF:

0.597

AC:

866613

AN:

1451680

Hom.:

261660

Cov.:

AF XY:

0.596

AC XY:

430950

AN XY:

722606

show subpopulations

Gnomad4 AFR exome

AF:

0.777

Gnomad4 AMR exome

AF:

0.716

Gnomad4 ASJ exome

AF:

0.633

Gnomad4 EAS exome

AF:

0.788

Gnomad4 SAS exome

AF:

0.612

Gnomad4 FIN exome

AF:

0.576

Gnomad4 NFE exome

AF:

0.578

Gnomad4 OTH exome

AF:

0.611

GnomAD4 genome

AF:

0.651

AC:

98970

AN:

151958

Hom.:

32861

Cov.:

AF XY:

0.652

AC XY:

48440

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.764

Gnomad4 AMR

AF:

0.668

Gnomad4 ASJ

AF:

0.627

Gnomad4 EAS

AF:

0.821

Gnomad4 SAS

AF:

0.632

Gnomad4 FIN

AF:

0.564

Gnomad4 NFE

AF:

0.582

Gnomad4 OTH

AF:

0.632

Alfa

AF:

0.612

Hom.:

18661

Bravo

AF:

0.664

Asia WGS

AF:

0.704

AC:

2453

AN:

3478

EpiCase

AF:

0.581

EpiControl

AF:

0.588

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Meckel syndrome, type 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Nephronophthisis 11

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Joubert syndrome 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

COACH syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.4

DANN

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00046

dbscSNV1_RF

Benign

0.14

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.

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