8-93755751-CTTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr8-93755751-C-CTTTTTTTTTT
• rs587779735
• NM_153704.6:c.224-12_224-3dupTTTTTTTTTT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_153704.6(TMEM67):​c.224-12_224-3dupTTTTTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 633,116 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000012 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: TMEM67 NM_153704.6 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.723
• Publications: 0 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

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.224-12_224-3dupTTTTTTTTTT		splice_acceptor intron	N/A	NP_714915.3
	TMEM67	NM_001142301.1		c.-62+629_-62+638dupTTTTTTTTTT		intron	N/A	NP_001135773.1
	TMEM67	NR_024522.2		n.245-12_245-3dupTTTTTTTTTT		splice_acceptor intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM67	ENST00000453321.8	TSL:1 MANE Select	c.224-12_224-3dupTTTTTTTTTT		splice_acceptor intron	N/A	ENSP00000389998.3
	TMEM67	ENST00000452276.6	TSL:1	c.224-12_224-3dupTTTTTTTTTT		splice_acceptor intron	N/A	ENSP00000388671.2
	TMEM67	ENST00000474944.5	TSL:1	n.244-12_244-3dupTTTTTTTTTT		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000117 AC: 1 AN: 85340 Hom.: 0 Cov.: 28

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: 0.0000241

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000694 AC: 38 AN: 547776 Hom.: 0 Cov.: 0 AF XY: 0.0000448 AC XY: 13 AN XY: 289910

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000896 AC: 1 AN: 11158

American (AMR) AF: 0.000147 AC: 3 AN: 20424

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 1 AN: 13028

East Asian (EAS) AF: 0.0000847 AC: 2 AN: 23616

South Asian (SAS) AF: 0.000212 AC: 9 AN: 42544

European-Finnish (FIN) AF: 0.0000913 AC: 3 AN: 32864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2162

European-Non Finnish (NFE) AF: 0.0000503 AC: 19 AN: 377416

Other (OTH) AF: 0.00 AC: 0 AN: 24564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000442313), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000117 AC: 1 AN: 85340 Hom.: 0 Cov.: 28 AF XY: 0.0000249 AC XY: 1 AN XY: 40174

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21870

American (AMR) AF: 0.00 AC: 0 AN: 8312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2250

East Asian (EAS) AF: 0.00 AC: 0 AN: 3072

South Asian (SAS) AF: 0.00 AC: 0 AN: 2568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 126

European-Non Finnish (NFE) AF: 0.0000241 AC: 1 AN: 41546

Other (OTH) AF: 0.00 AC: 0 AN: 1180

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72

Splicing

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

Other links and lift over

dbSNP: rs587779735; hg19: chr8-94767979;