ENST00000481620.1:n.345C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000481620.1(TMEM67):n.345C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 1,271,874 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 11 hom., cov: 31)

Exomes 𝑓: 0.0096 ( 119 hom. )

Consequence

TMEM67
ENST00000481620.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.637

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
COACH syndrome 1
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Meckel syndrome, type 3
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
nephronophthisis 11
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
COACH syndrome 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
Joubert syndrome 6
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Senior-Boichis syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMEM67 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 8-93755896-C-G is Benign according to our data. Variant chr8-93755896-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 262750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00676 (1023/151334) while in subpopulation SAS AF = 0.028 (134/4784). AF 95% confidence interval is 0.0242. There are 11 homozygotes in GnomAd4. There are 529 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.312+30C>G		intron_variant	Intron 2 of 27	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 link	c.312+30C>G		intron_variant	Intron 2 of 27	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

AF:

0.00675

AC:

1021

AN:

151218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00124

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.00501

Gnomad ASJ

AF:

0.00808

Gnomad EAS

AF:

0.0211

Gnomad SAS

AF:

0.0280

Gnomad FIN

AF:

0.00389

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.00775

Gnomad OTH

AF:

0.00720

GnomAD2 exomes

AF:

0.00970

AC:

2195

AN:

226180

AF XY:

0.0109

show subpopulations

Gnomad AFR exome

AF:

0.00153

Gnomad AMR exome

AF:

0.00343

Gnomad ASJ exome

AF:

0.00759

Gnomad EAS exome

AF:

0.0252

Gnomad FIN exome

AF:

0.00311

Gnomad NFE exome

AF:

0.00752

Gnomad OTH exome

AF:

0.00889

GnomAD4 exome

AF:

0.00957

AC:

10728

AN:

1120540

Hom.:

119

Cov.:

AF XY:

0.0103

AC XY:

5876

AN XY:

570750

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

26274

American (AMR)

AF:

0.00308

AC:

129

AN:

41824

Ashkenazi Jewish (ASJ)

AF:

0.00834

AC:

197

AN:

23612

East Asian (EAS)

AF:

0.0295

AC:

1098

AN:

37232

South Asian (SAS)

AF:

0.0278

AC:

2015

AN:

72384

European-Finnish (FIN)

AF:

0.00343

AC:

178

AN:

51918

Middle Eastern (MID)

AF:

0.0169

AC:

AN:

4682

European-Non Finnish (NFE)

AF:

0.00796

AC:

6480

AN:

813988

Other (OTH)

AF:

0.0107

AC:

518

AN:

48626

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

501

1002

1503

2004

2505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

246

492

738

984

1230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00676

AC:

1023

AN:

151334

Hom.:

Cov.:

AF XY:

0.00716

AC XY:

529

AN XY:

73924

show subpopulations

African (AFR)

AF:

0.00124

AC:

AN:

41294

American (AMR)

AF:

0.00501

AC:

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.00808

AC:

AN:

3466

East Asian (EAS)

AF:

0.0216

AC:

111

AN:

5148

South Asian (SAS)

AF:

0.0280

AC:

134

AN:

4784

European-Finnish (FIN)

AF:

0.00389

AC:

AN:

10288

Middle Eastern (MID)

AF:

0.0308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00775

AC:

526

AN:

67868

Other (OTH)

AF:

0.00713

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00752

Hom.:

Bravo

AF:

0.00652

Asia WGS

AF:

0.0270

AC:

AN:

3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 20, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.94

(source)

DANN

Benign

0.65

PhyloP100

-0.64

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over