Genetic Variant TMEM67:p.Met252Thr (chr8-93780633-T-C) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM5PP3PP5_Very_Strong

The NM_153704.6(TMEM67):c.755T>C(p.Met252Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M252V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:2

Conservation

PhyloP100: 7.39

Publications

23 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: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_153704.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-93780632-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2921894.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.787

PP5

Variant 8-93780633-T-C is Pathogenic according to our data. Variant chr8-93780633-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153704.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM67	NM_153704.6	MANE Select	c.755T>C	p.Met252Thr	missense	Exon 8 of 28	NP_714915.3
TMEM67	NM_001142301.1		c.512T>C	p.Met171Thr	missense	Exon 9 of 29	NP_001135773.1
TMEM67	NR_024522.2		n.776T>C		non_coding_transcript_exon	Exon 8 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.755T>C	p.Met252Thr	missense	Exon 8 of 28	ENSP00000389998.3
TMEM67	ENST00000452276.6	TSL:1	c.755T>C	p.Met252Thr	missense	Exon 8 of 27	ENSP00000388671.2
TMEM67	ENST00000474944.5	TSL:1	n.427-5590T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000835

AC:

AN:

251348

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000985

AC:

144

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000120

AC:

133

AN:

1112004

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000192

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000106

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Joubert syndrome 6 (2)

Joubert syndrome and related disorders (2)

Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 (1)

Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

TMEM67-related disorder (1)

Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.53

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.79

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

PhyloP100

7.4

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

0.38

Vest4

0.92

MVP

1.0

MPC

0.25

ClinPred

0.26

GERP RS

5.9

Varity_R

0.67

gMVP

0.95

Mutation Taster

=17/83

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over