rs967792092

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_153704.6(TMEM67):c.1289A>G(p.Asp430Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM67
NM_153704.6 missense, splice_region

Scores

Splicing: ADA: 0.0002795

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.88

Publications

1 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-93786223-A-G is Pathogenic according to our data. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-93786223-A-G is described in CliVar as Pathogenic. Clinvar id is 592161.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3291772). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM67	NM_153704.6 link	c.1289A>G	p.Asp430Gly	missense_variant, splice_region_variant	Exon 13 of 28	ENST00000453321.8	NP_714915.3	Q5HYA8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM67	ENST00000453321.8 link	c.1289A>G	p.Asp430Gly	missense_variant, splice_region_variant	Exon 13 of 28	1	NM_153704.6	ENSP00000389998.3		Q5HYA8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111828

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

RHYNS syndrome

Pathogenic:1

Dec 04, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.30

T;T;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Uncertain

-0.056

MutationAssessor

Benign

0.14

.;N;.;.

PhyloP100

2.9

PrimateAI

Benign

0.46

PROVEAN

Benign

0.13

N;N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.91

T;T;T;T

Sift4G

Benign

0.89

T;T;T;T

Polyphen

0.0010

.;B;.;.

Vest4

0.69, 0.41

MutPred

0.60

.;Gain of loop (P = 0.0312);.;.;

MVP

0.94

MPC

0.16

ClinPred

0.15

GERP RS

4.5

Varity_R

0.12

gMVP

0.69

Mutation Taster

=79/21

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00028

dbscSNV1_RF

Benign

0.056

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over