NM_153704.6:c.515G>T

Variant names:

• chr8-93765414-G-T
• rs750950408
• NM_153704.6:c.515G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_153704.6(TMEM67):​c.515G>T​(p.Arg172Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,040 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.75
• Publications: 11 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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 chr8-93765414-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217721.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758
• PP5: Variant 8-93765414-G-T is Pathogenic according to our data. Variant chr8-93765414-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2628355.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.515G>T	p.Arg172Leu	missense	Exon 5 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.272G>T	p.Arg91Leu	missense	Exon 6 of 29	NP_001135773.1
	TMEM67	NR_024522.2		n.536G>T		non_coding_transcript_exon	Exon 5 of 29

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.515G>T	p.Arg172Leu	missense	Exon 5 of 28	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.515G>T	p.Arg172Leu	missense	Exon 5 of 27	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.426+6838G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251282 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000548 AC: 8 AN: 1459040 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725844

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4156

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111336

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Meckel-Gruber syndrome;C0431399:Joubert syndrome Pathogenic:1

Feb 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 172 of the TMEM67 protein (p.Arg172Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TMEM67-related conditions. ClinVar contains an entry for this variant (Variation ID: 2628355). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg172 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19574260, 31019026, 34645491). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Joubert syndrome 6 Uncertain:1

Nov 10, 2023

Daryl Scott Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.7
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.56		Loss of disorder (P = 0.0755)
MVP		1.0
MPC		0.21
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.36
gMVP		0.92
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750950408; hg19: chr8-94777642;