rs201893408

Variant names:

• chr8-93795970-T-C
• rs201893408
• NM_153704.6:c.1843T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-93795970-T-C
• chr8-93795970-T-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM5 PP3_Moderate PP5_Very_Strong

The NM_153704.6(TMEM67):​c.1843T>C​(p.Cys615Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,613,072 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 (★★). ClinVar reports functional evidence for this variant: "SCV001427181: Transfected IMCD3 cells displayed impaired protein localization within the mid-cell region, and did not localize to the apical cell surface (Gunay-Aygun, M., et al. (2009))." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C615Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 7.25
• Publications: 24 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, 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001427181: Transfected IMCD3 cells displayed impaired protein localization within the mid-cell region, and did not localize to the apical cell surface (Gunay-Aygun, M., et al. (2009)).; SCV000475346: Functional studies in cell lines demonstrated that the p.Cys615Arg variant prevents the localization of the protein to cilia and disrupts the ability of TMEM67 to regulate Wnt signaling (Gunay-Aygun et al. 2009; Abdelhamed et al. 2015).; SCV004046149: Functional studies demonstrated that the p.Cys615Arg variant prevents localization and disrupts the ability of TMEM67 to regulate Wnt signaling (PMID: 19540516, 26035863).; SCV000567559: Published functional studies demonstrate C615R results in improper localization of the TMEM67 protein within cells (Gunay-Aygun et al., 2009; Abdelhamed et al., 2015); SCV000634630: Experimental studies have shown that this missense change affects TMEM67 function (PMID: 19540516, 26035863).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-93795971-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1349411.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 8-93795970-T-C is Pathogenic according to our data. Variant chr8-93795970-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1383.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	NM_153704.6	MANE Select	c.1843T>C	p.Cys615Arg	missense	Exon 18 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.1600T>C	p.Cys534Arg	missense	Exon 19 of 29	NP_001135773.1	Q5HYA8
	TMEM67	NR_024522.2		n.1864T>C		non_coding_transcript_exon	Exon 18 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.1843T>C	p.Cys615Arg	missense	Exon 18 of 28	ENSP00000389998.3	Q5HYA8
	TMEM67	ENST00000452276.6	TSL:1	c.1843T>C	p.Cys615Arg	missense	Exon 18 of 27	ENSP00000388671.2	C9JRQ8
	TMEM67	ENST00000474944.5	TSL:1	n.981T>C		non_coding_transcript_exon	Exon 9 of 17

Frequencies

GnomAD3 genomes AF: 0.0000919 AC: 14 AN: 152276 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000147 AC: 37 AN: 251362 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000904 AC: 132 AN: 1460796 Hom.: 0 Cov.: 31 AF XY: 0.0000922 AC XY: 67 AN XY: 726766

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1111114

Other (OTH) AF: 0.0000663 AC: 4 AN: 60348

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74402

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000187 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Joubert syndrome 6 (3)
3	-	-	TMEM67-related disorder (3)
1	-	-	Congenital ocular coloboma;C0028738:Nystagmus;C0030305:Pancreatitis;C0031154:Peritonitis;C0036857:Severe intellectual disability;C0040822:Tremor;C0264172:Barrel-shaped chest;C0557874:Global developmental delay;C1408258:Kidney damage;C1840379:Cerebellar vermis hypoplasia;C1854882:Absent speech;C1860834:Floppy infant;C3665347:Visual impairment;C4025708:Cerebellar malformation (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Joubert syndrome 6;C1865794:RHYNS syndrome;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 (1)
1	-	-	Joubert syndrome and related disorders (1)
1	-	-	Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C1865794:RHYNS syndrome;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 (1)
1	-	-	Meckel syndrome, type 3;C1853153:Joubert syndrome 6;C2673874:Bardet-Biedl syndrome 14;C3150796:Nephronophthisis 11;C5435651:COACH syndrome 1 (1)
1	-	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
1	-	-	Nephronophthisis 11 (1)
1	-	-	Oligohydramnios;C3887499:Renal cyst;C5979921:Joubert syndrome (1)
1	-	-	RHYNS syndrome (1)
-	-	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.035	D
Polyphen		0.98	D
Vest4		0.97
MVP		1.0
MPC		0.58
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.90
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs201893408; hg19: chr8-94808198;