NM_153704.6:c.2161C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_153704.6(TMEM67):c.2161C>T(p.Pro721Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,613,572 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P721R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 19 hom. )

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: -1.81

Publications

7 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, STRONG Submitted by: PanelApp Australia, 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: Ambry Genetics, Orphanet
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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004886687).

BP6

Variant 8-93799678-C-T is Benign according to our data. Variant chr8-93799678-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126302.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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	UniProt
TMEM67	NM_153704.6	MANE Select	c.2161C>T	p.Pro721Ser	missense	Exon 21 of 28	NP_714915.3
TMEM67	NM_001142301.1		c.1918C>T	p.Pro640Ser	missense	Exon 22 of 29	NP_001135773.1	Q5HYA8
TMEM67	NR_024522.2		n.2182C>T		non_coding_transcript_exon	Exon 21 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2161C>T	p.Pro721Ser	missense	Exon 21 of 28	ENSP00000389998.3	Q5HYA8
TMEM67	ENST00000452276.6	TSL:1	c.2161C>T	p.Pro721Ser	missense	Exon 21 of 27	ENSP00000388671.2	C9JRQ8
TMEM67	ENST00000474944.5	TSL:1	n.1299C>T		non_coding_transcript_exon	Exon 12 of 17

Frequencies

GnomAD3 genomes

AF:

0.00266

AC:

404

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000661

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00500

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00273

AC:

686

AN:

251328

AF XY:

0.00246

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00157

Gnomad NFE exome

AF:

0.00487

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00447

AC:

6536

AN:

1461358

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

3140

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33472

American (AMR)

AF:

0.00123

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.000881

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00545

AC:

6054

AN:

1111590

Other (OTH)

AF:

0.00376

AC:

227

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

301

602

904

1205

1506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<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:

0.00265

AC:

404

AN:

152214

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

194

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41536

American (AMR)

AF:

0.00150

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000661

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00500

AC:

340

AN:

68010

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00394

Hom.:

Bravo

AF:

0.00277

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00300

AC:

364

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00427

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Joubert syndrome 6 (1)

Meckel syndrome, type 3 (1)

Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Nephronophthisis 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.0080

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.36

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.62

M_CAP

Benign

0.029

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.59

MutationAssessor

Benign

-1.7

PhyloP100

-1.8

PrimateAI

Benign

0.23

PROVEAN

Benign

0.34

REVEL

Uncertain

0.30

Sift

Benign

0.70

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.061

MVP

0.75

MPC

0.12

ClinPred

0.0013

GERP RS

-11

Varity_R

0.023

gMVP

0.44

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over