NM_153704.6:c.2528A>G

Variant names:

• chr8-93808928-A-G
• rs386834194
• NM_153704.6:c.2528A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_153704.6(TMEM67):​c.2528A>G​(p.Tyr843Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,610,464 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 Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM67 NM_153704.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.17
• Publications: 2 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 8-93808928-A-G is Pathogenic according to our data. Variant chr8-93808928-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 56775.Status of the report is criteria_provided_single_submitter, 1 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.2528A>G	p.Tyr843Cys	missense	Exon 24 of 28	NP_714915.3
	TMEM67	NM_001142301.1		c.2285A>G	p.Tyr762Cys	missense	Exon 25 of 29	NP_001135773.1	Q5HYA8
	TMEM67	NR_024522.2		n.2549A>G		non_coding_transcript_exon	Exon 24 of 29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.2528A>G	p.Tyr843Cys	missense	Exon 24 of 28	ENSP00000389998.3	Q5HYA8
	TMEM67	ENST00000452276.6	TSL:1	c.2411A>G	p.Tyr804Cys	missense	Exon 23 of 27	ENSP00000388671.2	C9JRQ8
	TMEM67	ENST00000474944.5	TSL:1	n.1666A>G		non_coding_transcript_exon	Exon 15 of 17

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152088 Hom.: 0 Cov.: 32

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458376 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725754

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109014

Other (OTH) AF: 0.0000166 AC: 1 AN: 60270

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Meckel syndrome, type 3 (1)
1	-	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
1	-	-	TMEM67-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.74		Loss of MoRF binding (P = 0.0847)
MVP		1.0
MPC		0.63
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.62
gMVP		0.89
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs386834194; hg19: chr8-94821156;