dbSNP rs797046045: TMEM67:p.Lys99Asn (chr8-93755851-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2PM5PP5BP4

The NM_153704.6(TMEM67):c.297G>T(p.Lys99Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000007 in 142,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. K99R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000070 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM67
NM_153704.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.47

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, 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-93755850-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2932101.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 8-93755851-G-T is Pathogenic according to our data. Variant chr8-93755851-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212409.

BP4

Computational evidence support a benign effect (MetaRNN=0.3361599). . Strength limited to SUPPORTING due to the PP5.

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.297G>T	p.Lys99Asn	missense	Exon 2 of 28	NP_714915.3
TMEM67	NM_001142301.1		c.-62+714G>T		intron	N/A	NP_001135773.1	Q5HYA8
TMEM67	NR_024522.2		n.318G>T		non_coding_transcript_exon	Exon 2 of 29

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.297G>T	p.Lys99Asn	missense	Exon 2 of 28	ENSP00000389998.3	Q5HYA8
TMEM67	ENST00000452276.6	TSL:1	c.297G>T	p.Lys99Asn	missense	Exon 2 of 27	ENSP00000388671.2	C9JRQ8
TMEM67	ENST00000474944.5	TSL:1	n.317G>T		non_coding_transcript_exon	Exon 2 of 17

Frequencies

GnomAD3 genomes

AF:

0.00000700

AC:

AN:

142808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000260

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1379688

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

685540

African (AFR)

AF:

0.00

AC:

AN:

31172

American (AMR)

AF:

0.00

AC:

AN:

42310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23350

East Asian (EAS)

AF:

0.00

AC:

AN:

34560

South Asian (SAS)

AF:

0.00

AC:

AN:

81832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5318

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057384

Other (OTH)

AF:

0.00

AC:

AN:

55284

GnomAD4 genome

AF:

0.00000700

AC:

AN:

142808

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68898

show subpopulations

African (AFR)

AF:

0.0000260

AC:

AN:

38436

American (AMR)

AF:

0.00

AC:

AN:

13708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.00

AC:

AN:

4660

South Asian (SAS)

AF:

0.00

AC:

AN:

4374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66578

Other (OTH)

AF:

0.00

AC:

AN:

1966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000660

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

COACH syndrome 1 (1)

Joubert syndrome 6 (1)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.84

M_CAP

Benign

0.051

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.7

PhyloP100

1.5

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.29

Sift

Benign

0.062

Sift4G

Uncertain

0.038

Polyphen

0.98

Vest4

0.87

MutPred

0.49

Loss of methylation at K99 (P = 9e-04)

MVP

0.74

MPC

0.25

ClinPred

0.96

GERP RS

4.9

Varity_R

0.22

gMVP

0.89

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over