Genetic Variant NM_153704.6:c.2357G>T (chr8-93804796-G-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_153704.6(TMEM67):c.2357G>T(p.Gly786Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G786A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.47

Publications

6 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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_153704.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-93804796-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 684615.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.2357G>T	p.Gly786Val	missense	Exon 23 of 28	NP_714915.3
TMEM67	NM_001142301.1		c.2114G>T	p.Gly705Val	missense	Exon 24 of 29	NP_001135773.1
TMEM67	NR_024522.2		n.2378G>T		non_coding_transcript_exon	Exon 23 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2357G>T	p.Gly786Val	missense	Exon 23 of 28	ENSP00000389998.3
TMEM67	ENST00000474944.5	TSL:1	n.1495G>T		non_coding_transcript_exon	Exon 14 of 17
TMEM67	ENST00000452276.6	TSL:1	c.2322+1112G>T		intron	N/A	ENSP00000388671.2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151666

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250790

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454900

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33328

American (AMR)

AF:

0.0000224

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

85998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106114

Other (OTH)

AF:

0.00

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74056

African (AFR)

AF:

0.00

AC:

AN:

41286

American (AMR)

AF:

0.00

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67934

Other (OTH)

AF:

0.00

AC:

AN:

2086

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

PhyloP100

9.5

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.86

Loss of ubiquitination at K783 (P = 0.1166)

MVP

1.0

MPC

0.63

ClinPred

1.0

GERP RS

5.9

Varity_R

0.97

gMVP

0.96

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.58

Position offset: -34

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over